Article

ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 6, pp. 700-724 © Pleiades Publishing, Ltd., 2025.

Published in Russian in Biokhimiya, 2025, Vol. 90, No. 6, pp. 752-780.

700

REVIEW

Telomere Length and Telomerase Activity

as Biomarkers in the Diagnostics and Prognostics

of Pathological Conditions

Elizaveta Yu. Moskaleva

1,a

*, Alexander I. Glukhov

2,3,b

, Alexander S. Zhirnik

1,c

Olga V. Vysotskaya

1,d

, and Svetlana A. Vorobiova

2,e

Kurchatov complex for NBICS Sciences and Nature-like Technologies,

National Research Center “Kurchatov Institute”, 123182 Moscow, Russia

Department of Biological Chemistry,

I.M. Sechenov First Moscow State Medical University (Sechenov University),

119048 Moscow, Russia

Faculty of Biology, Lomonosov Moscow State University,

119991 Moscow, Russia

e-mail: Moskaleva_EY@nrcki.ru; moskalevaey@mail.ru

e-mail: aiglukhov1958@gmail.com

e-mail: as.zhirnik@mail.ru

e-mail: ovvysotskaya@mail.ru

e-mail: vorobeva_s_a@staff.sechenov.ru

Received March 20, 2025

Revised June 16, 2025

Accepted June 16, 2025

Abstract— Telomere biology still remains a topic of interest in life sciences. Analysis of several thousand

clinical samples from healthy individuals performed in recent years has shown that the telomere length (TL)

in peripheral blood leukocytes correlates with the TL in cells of internal organ and reflects their condition.

TLdecreases under the influence of damaging factors and can serve as an indicator of health status. Thetelo-

mere shortening leads to the cell proliferation arrest and is considered as a marker of replicative aging of

proliferating cells. A decrease in the TL in peripheral blood leukocytes is viewed as an indicator of organism

aging. Recent studies have allowed to formulate the concept on the role of the CST–polymerase α/primase

in the C-strand fill in after completion of 3′G overhang synthesis by telomerase during telomere replication.

The discovery of the telomeric RNA (TERRA) and its role in the regulation of telomerase activity (TA) and

alternative lengthening of telomeres, as well as the possibility of TERRA translation, has provided evidence of

the complex epigenetic regulation of the TL maintenance. Analysis of the published data indicates that telo-

meres are dynamic structures, whose length undergoes significant changes under the influence of damaging

factors. TL is determined not only by the chronological age, but also by the exposure to the exogenous and

endogenous deleterious factors during the lifetime. A decrease in the TL due to inherited mutations in the

genes coding for proteins involved in the telomere structure formation and telomere replication (primarily,

proteins of the shelterin and CST complexes and telomerase) has been found in a number of hereditary

diseases – telomeropathies. The assessment of TL and TA is of great importance for the diagnostics of telo-

meropathies and can be useful in the diagnostics of cancer. Analysis of TL can be used for monitoring the

health status (e.g., in the case of exposure to ionizing radiation and space flight factors), as well as predicting

individual’s sensitivity to the action of various damaging agents. The application of modern advancement in

genetic technologies in the analysis of TL and TA makes it available for the use in clinical and epidemiological

studies, diagnostics of telomeropathies, and monitoring of astronauts’ health.

DOI: 10.1134/S0006297925600814

Keywords: telomeres, telomerase, telomere length, CST–polymerase α/primase, shelterin complex, CST complex,

TERRA, ionizing radiation, radiosensitivity, oxidative stress, occupational irradiation, telomeropathies

* To whom correspondence should be addressed.

TELOMERE LENGTH AS PROGNOSTIC MARKER 701

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

INTRODUCTION

About 50 years ago, the Russian journal Proceed-

ing of the USSR Academy of Sciences (Doklady Aka-

demii Nauk SSSR) in 1971 and then the Journal of

Theoretical Biology in 1973 published the visionary

articles of the research scientist and theoretician Alex-

ey Matveevich Olovnikov (1936-2022), the author of

the terminal underreplication theory that explained

the shortening of the chromosomal ends with each

cell division [1, 2]. The ideas presented in these arti-

cles had been developed long before the discovery of

telomere shortening and its molecular mechanisms.

The studies of telomeres and mechanisms preserving

their length with the involvement of special poly-

merase have been initiated due to the publication of

the famous work by Leonard Hayflick, who stated that

normal somatic cells (fibroblasts) cultured in vitro are

unable to proliferate indefinitely and stop dividing af-

ter approximately 50 divisions [3].

To explain this phenomenon, Olovnikov suggest-

ed that during preparation for the cell division, the

chromosomal DNA cannot not be fully replicated and

becomes shorter at the ends after each doubling. DNA

shortening to a certain critical length causes the mal-

functioning of genes located close to the telomeres,

eventually leading to the cell death. According to the

theory of telomere aging, the shortening of chromo-

somal ends is a timer mechanism that determines the

number of cell divisions and explains the Hayflick limit.

These ideas have been confirmed by subsequent

discoveries. First, Greider and Blackburn found a new

enzyme, telomere terminal transferase (later named

telomerase), in the extracts of Tetrahymena cells [4].

The same authors demonstrated that telomerase con-

tains RNA essential for the synthesis of telomeric re-

peats [5]. Inspired by the work of Olovnikov, CarolW.

Greider conducted similar studies in human fibro-

blasts [6], resulting in the discovery of telomerase in

human cells and cells of other eukaryotic organisms.

It was demonstrated that the aging of cultured hu-

man fibroblasts was indeed accompanied by telomere

shortening [7, 8]. The results obtained by Greider and

Blackburn, who were awarded the Nobel Prize in

Physiology or Medicine in 2004, have fully proven the

Olovnikov’s hypothesis on the mechanisms of somatic

cell aging. Moreover, these studies have opened a new

era in the research of the role and mechanisms of telo-

mere length (TL) maintenance in normal cells and in

various pathological processes, including those caused

by deleterious factors, such as ionizing radiation (IR),

and space flight factors. Biochemistry (Moscow) [9]

and Biogerontology [10] have dedicated special issues

to the memory of A.  M.  Olovnikov and modern devel-

opments in the concepts of telomere structure he had

predicted.

The structure of chromosomal telomeric regions

is characterized by a number of features that make

them particularly sensitive to the effects of genotoxic

factors. A decrease in the TL can lead to irreversible

disturbances in cell functioning and can serve as a

marker for the individual’s increased sensitivity to the

effects of endogenous and exogenous damaging fac-

tors. Current achievements in biochemistry and mo-

lecular genetics and introduction of methods for the

analysis of large amounts of data have significantly

expanded the possibilities of medical and biological

studies of the state of telomeres.

The aim of this review was to analyze the results

of studies on the mechanisms of telomere mainte-

nance in human cells under the influence of damag-

ing factors and in diseases caused by disturbances in

the telomere biology. Such analysis can be helpful in

selection of prognostic markers of the increased sen-

sitivity of patients to radiotherapy and chemotherapy,

which would allow to evaluate the risk of developing

unwanted late complications. Here, we addressed cur-

rent concepts on the telomere structure, mechanisms

of TL maintenance, regulation of telomerase activi-

ty (TA), telomere sensitivity to irradiation, oxidative

stress, and space flight factors, state of the TA-TL sys-

tem, and technologies for the TA and TL assessments

that can be used in clinical and epidemiological stud-

ies.

TELOMERE STRUCTURE AND MECHANISMS

OF TELOMERE MAINTENANCE

Telomere structure. Telomeres are specialized

DNA sequences at the ends of eukaryotic chromo-

somes. In humans, they consist of the repeating

non-coding six-nucleotide sequence TTAGGG. The un-

derreplication of chromosomal DNA due to the prop-

erties of DNA polymerase functioning results in the

generation of free single-stranded GGG overhangs at

the telomere 3′-ends in the course of DNA replication.

During DNA replication in the S phase of the cell cy-

cle, telomeres exist in the open linear form, while in

other phases of the cell cycle, telomeres form loops

that close the ends of the chromosomes (Fig. 1).

Electron microscopy studies of the in situ con-

figuration of human and mouse telomeric DNA [11]

showed the presence of large loops formed by fold-

ing back the telomere ends. The circular segment

of the loops consisted of the telomeric DNA duplex

called the T-loop. The invasion of the 3′ telomeric

overhang into the duplex telomeric repeat array re-

sults in the displacement of the TTAGGG repeat strand

at the loop-tail junction. Based on the binding with

a single-stranded DNA, this displacement loop of

TTAGGG repeats (D-loop, Fig.  1) was deduced to be

MOSKALEVA et al.702

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Fig. 1. Open telomere and telomere as the T-loop with D-loop at the site of the single-stranded telomere overhang inser-

tion (a); the binding of shelterins to the double-stranded (TRF1 and TRF2) and single-stranded (POT1) telomeric DNA (b).

Shelterin complex proteins cover the entire telomere. According to [11, 15].

approximately several hundred nucleotides long in

many T-loops. Although the exact site of the 3′-end

invasion has not been identified, in most cases the

loop was very large (many kilobases) and sometimes

encompassed the entire telomere. A close correlation

was found between the length of the telomeric repeats

and the T-loop size [11]. Figure1 shows the structure

of the T-loop and provides a general overview of how

the loops can form to protect the telomeric ends, al-

though the possibility of a different organization of

the loops cannot be ruled out [12, 13].

Human telomeres contain a large number of

G-quadruplexes (G4s). G4s are non-canonical four-

stranded structures that can form in guanine-rich

DNA and RNA sequences. The core structure of G4s

consists of stacked guanine tetrads (G-tetrads), square

planar platforms of four guanine bases held togeth-

er by Hoogsteen hydrogen bonds. Formation of G4s

requires cations, in particular, K

or Na

, to stabilize

the stacked guanine tetrads through coordination with

the O6 atoms in guanines. G4s can promote the T-loop

formation and provide intermolecular DNA–RNA in-

teractions [14].

An important role in the formation and stabili-

zation of T-loops and, thus, in the protection of telo-

meric ends, belongs to the proteins of the shelterin

complex (Fig. 1b) [15-18]. These proteins bind to the

telomeric DNA and determine the shape of the telo-

meric ends. They protect telomeres from the action of

DNA repair enzymes and perform a number of other

functions resulting in telomere protection [15, 17, 19].

The shelterin complex consists of six proteins listed

in Table 1.

The POT1–TPP1 complex is a structural compo-

nent of the telomere that increases the activity and

processivity of telomerase core enzyme and provides

the TL increase during DNA replication [21, 22].

Telomeres are also associated with a number

of proteins (Mre11/Rad50/Nbs1, ERCC1/XPF, DNA-PK,

PARP2) involved in recombination and DNA repair,

including homologous recombination repair. These

proteins interact with the shelterin complex proteins

and participate in the formation and maintenance of

T-loops [15]. Beside the formation of T-loops to prevent

the recognition of chromosomal ends as double-strand

DNA breaks (DSBs), other cellular mechanisms have

been discovered that suppress the development of the

DNA damage response (DDR) at the telomeres. These

mechanisms involve proteins of the shelterin complex

and have been described in detail in [12, 17, 23].

In his discussion of the connection between the

telomere shortening, decreased cell survival, and

aging, Yegorov [24] pointed out the strained confor-

mation of DNA in the T-loop. Gradual shortening of

telomeric DNA may come to a point when the TL

becomes insufficient for the telomeric DNA to form

a loop. The telomere acquires a free open conforma-

tion and is perceived by the cell as a DSB, which trig-

gers the DDR and results in telomere damage [24].

This hypothesis explains the connection between the

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Table 1. Structural proteins of the shelterin complex and their functions [15, 20]

Abbreviation Full name Protein function

TRF1 telomere repeat factor 1

TRF1 homodimer binds to the double-stranded

TTAGGG telomere region and inhibits telomere

elongation by telomerase

TRF2 telomere repeat factor 2

TRF2 homodimer binds to the same region as TRF1,

but prevents recognition of double-strand DNA breaks

(DSBs) as a type of DNA damage that requires repair

POT1 protection of telomere 1

exhibits affinity for single-stranded guanine-rich

telomere regions, protects them from nucleases

RAP1 repressor/activator protein 1 stabilizes TRF2

TIN2

TRF1- and TRF2-interacting

nuclear protein 2

stabilizes the complex of TPP1-POT1 with TRF1 and TRF2

TPP1 (TINT1,

PTOP, PIP1)

telomere-protecting protein 1 binds POT1 to TIN2 and is required for POT1 functioning

decrease in the TL, arrest of cell proliferation, and

cell aging and death.

During each cell cycle, telomeres shorten by 50-

150bp at the DNA replication stage [25]. Critical short-

ening of telomeres impairs their function, leading to

the cell aging or apoptotic death. Chromosomes lack-

ing telomeres may undergo further shortening, result-

ing in the loss of coding genes or fusion with other

chromosomes, which causes genetic instability and in-

creases the risk of cell malignant transformation [26].

A decrease in the TL or prolonged DDR lead to the

cessation of proliferation and activation of cell senes-

cence. Senescent cells actively secrete proinflammato-

ry cytokines (IL-6, IL-8, TNFα, IL-1, and CCL), growth

factors (HGF and IGFBP), metalloproteinases (enzymes

that degrade the extracellular matrix), reactive oxy-

gen species (ROS), and nitric oxide, i.e., acquire the

so-called senescence-associated secretory phenotype

(SASP). The cytokines secreted by senescent cells can

induce senescence of neighboring cells and provoke

body aging [27-29]. Therefore, telomere shortening

can be considered as a marker of replicative aging of

proliferating cells, while stable TL is an indicator of

a healthy state.

The TL as a biomarker of aging or some pathol-

ogies is typically assessed in leukocytes or peripheral

blood lymphocytes. Analysis of human tissues from

the Genotype-Tissue Expression (GTEx) Project collec-

tion [30,  31] allowed to characterize the TL in more

than 6300 samples from over 20 tissue types obtained

from 952 individuals. It was shown that variations in

the TL are determined by the tissue type, donor, do-

nor age, and to a lesser extent by race or ethnicity,

smoking, and hereditary variants. Generally, the TL in

the whole blood cells correlated with the TL in most

tissues. The TL was the shortest in the whole blood

cells and the longest in the testis. In most tissues, the

TL was inversely associated with age, and this associ-

ation was the strongest in the tissues with a shorter

average TL. The results of this study demonstrated

that changes in the TL in the blood cells reflected the

TL features characteristic of all other tissues of an

examined individual [31].

Similar results were obtained for the compari-

son of the TL in human brain and peripheral tissues

[32]. DNA was isolated from saliva, buccal epitheli-

um, blood, and brain tissue from the patients under-

going neurosurgery for the intractable epilepsy, and

average TL was assessed by qPCR. The highest cor-

relation was detected between the TL values in the

brain and buccal samples. This study was unique, be-

cause the authors were able to directly compare the

TL in the brain and peripheral tissues from living

subjects. The correlation between the TL values in si-

multaneously collected buccal samples and leukocytes

was sufficient to suggest the use of buccal DNA as a

reliable non-invasive source for determining the TL

in humans [33].

Currently, the TL is commonly considered as an

indicator of human health. The maximal TL is ob-

served in children at the age of 18 months. Then, the

TL rapidly decreases, gets stabilized by the age of 5,

and remains at ~12  kb until the age of 25. After this,

the TL steadily decreases and could reach 5  kb by the

age of 80 [34, 35]. The TL depends not only on the

age, but also on the individual’s genetic features and

the action of various damaging factors experienced by

a person throughout the lifetime.

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Fig. 2. The role of CST–Polα/Prim in the synthesis of telomere ends. Telomerase elongates the G-overhang of the leading DNA

strand, while CST–Polα/Prim fills in the complementary C-strands of the lagging and leading DNA strands at the telomere end.

When the replisome reaches the telomere end, the synthesis of the last Okazaki fragment begins >40nucleotides (nt) from

the site of the double-stranded DNA unwinding (according to [46]). Polδ and Polε are DNA polymerases δ and ε, respectively.

Telomere maintenance mechanisms. As men-

tioned above [4, 7], the TL in proliferating cells is

maintained by telomerase and CST–Polymerase  α/pri-

mase (CST–Polα/Prim) [36,  37]. In some normal and tu-

mor cells, the TL is maintained by the homologous re-

combination of telomeric DNA. During this process, the

3′ overhang of a short telomere of one chromosome is

inserted into the telomere of another “long” chromo-

some and uses it as a template for DNA synthesis with

the participation of enzymes and factors required for

homologous recombination. This mechanism is called

alternative lengthening of telomeres (ALT) [26,  38,  39].

Under certain conditions (e.g., when DNA is dam-

aged), the elongation of telomeres may switch from

the telomerase-catalyzed process to the ALT [40]. In

most proliferating cells, the main mechanism of the

TL maintenance is the synthesis of telomeric DNA by

telomerase and CST–Polα/Prim, but under stress con-

ditions, even these cells can simultaneously use the

ALT mechanism.

Telomerase and CST–polymerase α/primase. Telo-

merase is a ribonucleoprotein complex consisting of

the catalytic subunit (telomerase reverse transcriptase,

TERT) and the RNA component (TR, or TERC) that acts

as a template for the synthesis of telomeric repeats

at the ends of eukaryotic chromosomes [4, 7]. The

template for the synthesis of telomeric repeats in the

hTR is the 5′-CUAACCCU-3′ sequence. The template

binds complementarily to the protruding 3′ end of

the telomere and is used to synthesize new telomeric

5′-TTAGGG-3′ repeats in vertebrates [41-43]. Telomer-

ase adds G-rich telomeric repeats (TTAGGG)

to the

3′ ends of telomeres, thereby counteracting telomere

shortening caused by the loss of telomeric 3′ over-

hangs during the synthesis of the DNA leading strand.

However, telomerase does not compensate for the loss

of DNA sequence at the 5′ ends of chromosomal DNA,

which occurs during the synthesis of the lagging DNA

strand, as well as by partial degradation of the termi-

nal fragments of telomeric DNA by nucleases.

Until recently, the mechanism of synthesis of

the (CCCTAA)

ends of the telomere complementary

C-strand had remained poorly understood [44]. In re-

cent years, several excellent experimental papers and

reviews on this problem have been published [36, 37,

45, 46].

The replication of the C-strand end region of telo-

meres in vivo requires the CST protein complex that

acts as an auxiliary factor for the activity of CST–Polα/

Prim received its name from the first letters of the

names of proteins in its content: CTC1 (conserved telo-

mere component  1), STN1 (suppressor of cdc thirteen),

and TEN1 (telomeric pathways in association with

STN1, number  1) [44, 47]. The elongation of telomeres

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BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

begins at the end of the S phase. First, the 3′  G-end is

elongated by telomerase, and then the complementary

C-strand is synthesized by CST–Polα/Prim (Fig. 2).

Regulation of telomerase activity. The catalytic

core of human telomerase exists invivo as a function-

ally cooperative dimer of two reverse transcriptase

subunits (hTERT and hTR) or as a multimer [48]. In

addition to the proteins of the shelterin and CST com-

plexes, hTERT can bind p23/p90 (a chaperone respon-

sible for the complex assembly and conformation),

nuclear localization protein 14-3-3, and TP1 protein

with an unknown function [49]. hTR can bind hGAR1,

Dyskerin/NAP57, hNHP2, and C1/C2 (proteins responsi-

ble for the RNA stability, maturation, and localization),

proteins providing binding to the telomeres, and some

other proteins [50].

The gene coding for hTERT consists of 16 exons.

Its length is 37  kb, of which ~33  kb are introns and

the rest ~4  kb encodes the transcript [51]. The TA can

be regulated through different mechanisms, including

gene expression, phosphorylation/dephosphorylation,

alternative splicing, etc. [52,  53]. Humans express

more than 20 telomerase isoforms. The N-terminal

fragment of telomerase contains the nuclear localiza-

tion signal, RNA interaction domains, and a sequence

that directs it to the mitochondria. The C-terminal

part contains regions that determine the reverse

transcriptase activity of hTERT. In most telomerase

isoforms, these critical elements of protein structure

are disrupted to various degrees. Only the full-length

enzyme, whose mRNA contains all 16 exons, displays

a high TA. All known hTERT splice variants in hu-

man and mouse cells are inactive and, moreover, in-

hibit the TA. This suggests that the hTERT isoforms

formed by alternative splicing, play an important role

in the TA regulation and implementation of telomer-

ase non-canonical functions unrelated to its catalytic

activity [54].

The recruitment of telomerase to telomeres is me-

diated by the shelterin complex proteins POT1–TPP1

[42], whereas timely termination of telomere elonga-

tion occurs with involvement of the CST heterotri-

meric complex composed of the CTC1, STN1, and TEN

proteins [55, 56]. The CST complex competes with the

telomerase processivity factors POT1–TPP1 for binding

to the single-stranded region of telomeric DNA and

inhibits the TA by preventing enzyme binding to the

single-stranded region of DNA and its physical inter-

action with POT1–TPP1. The binding of the CST com-

plex to the telomere increases during the late S/G2

stages only when the telomerase is active and results

in the inhibition of its activity. Removal of the CST

complex leads to the excessive TA and promotes ex-

cessive telomere elongation. By binding to the elon-

gated telomere, the CST complex interrupts the action

of telomerase. Therefore, the elongation of the telo-

mere 3′ G-end is determined by the sequence of three

events (Fig. 2) which first turn on and then stop the

telomerase-mediated telomere elongation: (i)telomer-

ase recruitment to telomeres in the region of the sin-

gle-stranded 3′ G-end with participation of the POT1–

TPP1 proteins; (ii)elongation of the telomere 3′ G-end

by telomerase; (iii) displacement of the POT1–TPP1

proteins from the complex with the single-stranded

3′ G-end by the CST complex and blockade of telo-

merase binding to the 3′ G-overhang, resulting in the

cessation of telomere elongation [37, 45, 47, 49]. The

synthesis of the complementary C-strand by CST–Polα/

Prim begins after completion of the G-strand elon-

gation [46, 57].

Hence, the CST complex plays a key role in the

regulation of two steps of telomere replication: termi-

nation of the G-strand elongation by telomerase and

recruitment of CST–Polα/Prim to the newly synthe-

sized G-overhang and its activation for the synthesis

of the complementary C-strand.

A long non-coding RNA with the telomeric repeats

at the 3′ end, called TERRA (telomeric repeat-contain-

ing RNA), may play an important role in the TA reg-

ulation at the epigenetic level [58] (see reviews [59,

60] for the TERRA formation and properties). It was

shown that telomeres can be actively transcribed by

RNA polymerase II from promoters located in the

subtelomeric regions in the direction from the cen-

tromere toward the end of telomeres with the forma-

tion of the TERRA. The length of this RNA can vary

from 100nt to 9 kb [58]. The 5′-UUAGGG-3′ repeats in

TERRA interact with the hTR sequence. In addition,

TERRA binds to the TERT protein independently of its

interaction with hTR. TERRA is not used as a telomer-

ase substrate. Instead, it acts as a potent competitive

inhibitor of telomerase interaction with the telomer-

ic DNA [61]. TERRA colocalizes with the telomerase

hTR in the nucleoplasm and at telomeres at different

phases of cell cycle.

Most TERRA molecules are diffusely located in

the nucleoplasm. One of the functions of this soluble

pool is telomerase binding and regulation of its activ-

ity. TERRA controls the TL homeostasis by regulating

the TA at the telomeres. High TERRA expression was

found to correlate with the content of short telomeres

in various cell lines, which supports the model of

TERRA as a negative regulator of TA [62].

TERRA may be regarded as a structural compo-

nent of the telomere binding to the telomere through

the shelterin complex proteins TRF1 and TRF2, het-

erochromatin protein  1, histone H3trimethylK9, and

some other proteins [63]. Telomeric DNA exists in the

cell as a component of heterochromatin. TERRA is

currently considered as a key regulator of telomere

maintenance and heterochromatin formation at telo-

meres [59, 63].

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BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Xu and Komiyama [64] summarized the data

on the structure and conformation of G4s in DNA,

RNA, and DNA–RNA hybrids in human telomeres

and showed that TERRA plays a crucial role in the

telomere capping through the formation of telomer-

ic G4s [64]. Notably, TERRA exhibits a preference for

the formation of G4s in the DNA–RNA hybrids at the

3′end of telomeric DNA. Intramolecular G4s with dif-

ferent folding structures and loop conformations and

experimentally determined molecular structures have

been shown for the parallel, hybrid, and basket G4s

in [14, 64] and for intermolecular hybrid DNA–RNA

G4s in [64]. It should be noted that G4s are mobile

structures capable of unfolding, in particular, with

the participation of POT1 protein  [65]. Some small

G4 ligands stabilize G4s, resulting in telomerase in-

hibition [66]. Telomere damage triggers TERRA tran-

scription, so that the upregulation of TERRA can be

considered as a molecular marker of telomere desta-

bilization [67].

TERRA can form RNA–DNA hybrids with the cyto-

sine-rich telomeric DNA strands. The telomeric strand

containing the TTAGGG repeats is displaced, resulting

in the formation of the R-loop structure  [68] crucial

for the telomere maintenance  [69]. Excessive TERRA

R-loops can cause replicative stress, chromosome dam-

age, and loss of telomeres [69,  70]. TERRA and TERRA

R-loops are highly abundant in human cancer cells, in

which telomere elongation occurs via the ALT mech-

anism [71].

It has been recently shown that translation of

TERRA yields two proteins consisting of repeating

dipeptides: a highly charged protein formed by va-

line-arginine (VR) repeats and a hydrophobic pro-

tein formed by the glycine–leucine (GL) repeats [72].

The VR protein binds nucleic acids and localizes at

the replication forks. Both VR and GL proteins form

long 8-nm filaments with the amyloid properties. The

authors showed that cells with the elevated levels of

TERRA in the nuclei contained three to four times

more VR protein than the original cell line. Deletion

of TRF2 caused the dysfunction of telomere and in-

creased the content of VR protein, while manipulation

of TERRA levels using specific approaches resulted in

the appearance of large VR aggregates in the nucle-

us. These data suggest that telomeres, particularly in

cells with dysfunctional telomeres, can express two

unusual dipeptide-repeat proteins with potentially

important biological properties [72]. These new find-

ings suggest that despite extensive research into the

role of TERRA in the regulation of telomere function,

many unanswered questions still remain.

Alternative functions of TERT and TR. The exten-

sive studies of telomerase have provided new data

on the functions of holoenzyme components that are

not associated with the telomere elongation per  se,

but play an important role in ensuring cell survival

under the influence of damaging factors. Both TERT

and TR may be involved in the regulation of various

intracellular processes, including gene expression and

stress response.

Alternative functions of TERT have been dis-

cussed in [43, 73-76]. An important property of TERT is

its ability to protect cells from the damage caused by

oxidative stress. Alternative functions of TERT include

not only the antiapoptotic and antioxidant effects,

but also the protection against specific DNA-damag-

ing agents. TERT can translocate between the nucleus,

cytoplasm, and mitochondria due to the nuclear ex-

port signal identified at the protein N-terminus. In the

case of oxidative stress, TERT is phosphorylated at the

tyrosine residue 707 by the Src kinase, which triggers

its nuclear export. In addition, TERT contains a spe-

cific N-terminal 20-amino acid sequence that serves

as a mitochondrial localization signal. The transport

of TERT into the mitochondrial matrix involves trans-

locases of the outer and inner mitochondrial mem-

branes.

The role of TERT in the mitochondria was dis-

cussed in [75]. hTERT-overexpressing non-prolifer-

ating human fibroblasts were characterized by the

reduced ROS generation and upregulated expression

of antioxidant defense proteins. In these cells, the ox-

idative stress induced by X-rays or H

caused less

damage to the mitochondrial membrane potential and

mitochondrial morphology than in normal fibroblasts.

Both genotoxic factors (X-rays and H

) significant-

ly increased the number of γH2AX foci (phosphory-

lated form of H2AX histone, DNA damage marker).

The DNA damage induced by X-ray irradiation in the

control cells persisted for many days, while in the

hTERT-overexpressing fibroblasts, this damage was

considerably less and DNA was fully repaired within

the following days.

It should be noted that the early studies on the

telomerase content in different tissues have shown the

presence of hTERT in proliferating cells, while hTR

has been found in almost all tissues [41], suggesting

that hTR may have the functions unrelated to the

TA regulation. It was later discovered that the hTR

knockdown reproducibly induced apoptosis in the ab-

sence of any detectable telomere shortening or DDR

activation. In contrast, the knockdown of hTERT did

not induce apoptosis [76]. The authors suggested that

hTR can function as a non-coding RNA that protects

cells from apoptosis independently of its involvement

in telomere lengthening by telomerase in normal hu-

man cells [76].

Possible non-telomeric functions of hTR have

been discussed in reviews [77, 78]. Numerous studies

have provided evidence on the implication of hTR in

protective mechanisms. Thus, hTR contains an open

TELOMERE LENGTH AS PROGNOSTIC MARKER 707

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Fig. 3. Telomerase functions in the cell. The TL is maintained through the synthesis of telomeric DNA by telomerase or

via the ALT pathway, which is necessary for the T-loop formation and chromosome preservation. Telomerase components

TERT and TR possess the protective functions. TERT can migrate to the mitochondria and increase the level of antioxidant

defense and anti-apoptotic activity in these organelles. TR can serve as a template for the synthesis of TERP protein, which

exhibits the anti-apoptotic activity. TERRA reduces the TA and stimulates the ALT pathway to maintain the TL.

reading frame that starts at position 176 and codes

for a 121-amino acid protein named hTERP. hTERP is

encoded as an immature transcript. The existence of

hTERP has been confirmed by several experimental

approaches including mass spectrometry and immu-

nodetection [79]. The overexpression of the wild-type

hTR (but not its mutant version incapable of directing

hTERP synthesis due to mutation in the start codon)

protected HEK293T cells from the doxorubicin-induced

apoptosis. hTERP may be involved in cell protection

from stress and promotion of cell survival under the

action of damaging factors and during adaptation to

unfavorable conditions. This alternative activity of

telomerase components may play an important role

in ensuring cell survival under the influence of dele-

terious factors.

The known functions of telomerase ensuring cell

stability are shown in Fig. 3.

Therefore, the maintenance of TL in proliferating

cells by telomerase and CST–Polα/Prim or via the ALT

mechanism, the antiapoptotic activity of telomerase

components TERT and TR, and the antioxidant activity

of TERT in the mitochondria provide cell resistance to

the action of damaging factors.

Telomerase and telomere maintenance in tumors.

Telomerase expression is suppressed in resting cells,

but is reactivated upon their malignant transforma-

tion. High expression of telomerase gene and high TA

have been detected in various types of malignant tu-

mors [26,  52,  80]. Therefore, the presence of TA in a

tissue extract can be used as a marker in the diagnos-

tics of malignant tumors. Unlimited cell proliferation

facilitated by telomerase reactivation is a hallmark of

cancer, as it enables long-term proliferation of cells

with short telomeres.

In 5-15% tumors, the TL is maintained by the ALT

mechanism [26,  38,  81]. ALT is frequently found in

tumors of mesenchymal origin: in 60% of soft tissue

sarcomas, 100% of chondrosarcomas, 63% of undiffer-

entiated pleomorphic sarcomas, 53% of undifferenti-

ated leiomyosarcomas, and 14% of fibrosarcomas. In

CNS tumors, ALT was found in 63% of diffuse and

anaplastic astrocytomas and in 44% of glioblastoma

multiforme in children (but only in 11% tumors in

adults).

No association between the TL in peripheral

blood leukocytes and risk of cancer development has

been established for solid cancers [82]. At the same

time, there is a correlation between the reduced TL

in leukocytes and various hematological malignancies

[83]. Therefore, the assessment of TL and TA for the

diagnosis and prognostics of cancer should be per-

formed only in tumor biopsies or surgically removed

tumor tissues.

MOSKALEVA et al.708

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

The high level of TA in malignant tumors may

be due to mutations in the TERT gene promoter or

genes coding for the shelterin and CST complex pro-

teins; itcan also be determined by specific expression

patterns of numerous transcription factors that regu-

late the TA [84].

The use of TA analysis in the early diagnostics of

bladder cancer seems particularly promising due to

the possibility of non-invasive TA measurement in the

urine. Therefore, the TA assay might become a gold

standard for the non-invasive diagnostics of bladder

cancer [85, 86].

A pilot study demonstrated a high value of the

urine and tissue TA levels (measured by RT-TRAP-

2PCR) in detection and monitoring of bladder cancer.

An association was found between the tumor size

(≥3  cm) and elevated TA levels in tissues and urine.

However, no such correlation was observed between

the higher TA levels and tumor grade/size at the ad-

vanced cancer stages [87,  88]. It should be noted that

TA assays are available, but they have not yet been

introduced into clinical practice because of the high

cost and problems with the standardization of pro-

cedures for the sample collection and preparation.

At the same time, preparation of samples for the cur-

rently used histological examination is less compli-

cated and can be automated. A more promising ap-

proach for the diagnostics of malignant tumors and

monitoring of the therapy efficacy is a rapidly devel-

oping analysis of specific marker mutations in liquid

biopsies. For example, the C228T and C250T mutations

in the TERT gene promoter play an important role

in the malignant transformation of cells and can be

used as biomarkers in many types of cancer, including

glioblastoma multiforme, as they are detected in 80%

of glioblastoma multiforme cases [89, 90].

To summarize the above, we should emphasize,

in most proliferating cells the TL is maintained by

telomerase and CST–Polα/Prim with the participation

of DNA polymerases δ and ε. The TA is regulated at

the transcriptional level, by post-transcriptional mod-

ifications, and epigenetically. Proteins of the shelterin

and CST complexes, as well as numerous other pro-

teins and regulatory factors involved in the TL main-

tenance, have been intensively explored. At the same

time, the telomerase components hTERT and hTR

perform a number of functions aimed at increasing

cell resistance to the stress factors. In some cells and

tumors, the TL is maintained through the ALT mech-

anism. Reactivation of telomerase during malignant

cell transformation ensures the long-term prolifera-

tion of tumor cells with short telomeres. The pres-

ence of TA and mutations in the hTERT gene promoter

(C228T and C250T) may be the hallmarks of malignant

tumors, with the exception of sarcomas and some

brain tumors.

TELOMERE SENSITIVITY

TO IONIZING RADIATION

DNA damage and telomere DNA repair. Among

the types of molecular damage caused by IR, forma-

tion of DSBs in DNA has the most severe consequences

for the cells, because persistence of unrepaired DSBs

leads to cell death. DSB repair occurs through the two

main mechanisms: homologous recombination, which

occurs only during the S and G2 phases of cell cycle,

and classical non-homologous end joining (c-NHEJ)

that takes place during all phases of cell cycle [91-93].

In mammalian cells, DSBs are repaired by both c-NHEJ

and homologous recombination mechanisms. The cells

can also use the alternative end-joining mechanism,

which is associated with the loss of nucleotides, re-

quires the presence of homologous sequences in the

same chromosome, and leads to the appearance of er-

rors in the DNA structure. Alternative end-joining is

a less studied mechanism; however, it is known to in-

volve PARP1, DNA polymerase θ, Lig1 ligase, and Lig3–

XRCC1 complex [91-95]. It is employed when c-NHEJ or

homologous recombination cannot function properly.

In addition to the above-mentioned mechanisms,

DSBs can be repaired via the RAD51-independent ho-

mology-dependent single-strand sequence annealing,

i.e., joining of the ends of two homologous 3′  single-

stranded DNA fragments in the region of tandem

sequences, which leads to the obligatory removal of

DNA fragment between the repeats. This mechanism

functions only during the S and G2 phases of cell cy-

cle and is associated with the appearance of errors in

DNA and increased frequency of mutations [93].

The development of DDR in the telomere region

can lead to the disturbances in the telomere structure;

however, reactions that are dangerous for the cell

can be suppressed by the shelterin complex proteins

(Table1). Thus, TRF2 binds the ATM kinase and inhibits

the ATM-dependent DDR [96]. It was found that TRF2

interacts with DDR factors not only at the telomeres,

but also in other chromosomal regions. Phosphoryla-

tion of TRF2 at serine 20 reduced its binding affini-

ty to the telomeres and promoted TRF2 relocation to

non-telomeric DSBs, thus facilitating their repair [97].

Another protein of the shelterin complex, POT1,

prevents activation of the ATR kinase involved in the

single-stranded DNA repair, thus arresting DDR in the

telomeres [98]. TRF2 and POT1 act independently to

suppress the two DDR pathways. It was found that

X-ray irradiation of fibroblasts was followed by a

long-term presence of DDR markers at the telomeres,

while in other chromosomal regions, such damage

was quickly eliminated by DNA repair. No telomere

shortening was observed [28, 99]. The prolonged

presence of unrepaired DSBs in the telomeric DNA

leads to the DDR persistence, arrest of proliferation,

TELOMERE LENGTH AS PROGNOSTIC MARKER 709

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

and activation of cell senescence [27, 29]. There is ev-

idence that TERRA is also involved in the regulation

of DSB repair in DNA [100, 101].

The features of the telomere response to DNA

damage have been discussed in detail in comprehen-

sive reviews [12, 13, 15, 17]. As telomeres constitute

only a small fraction of the human genome, the proba-

bility that photons or accelerated particles will direct-

ly cross the telomeric sequence is very low. Therefore,

the IR-induced telomere damage likely occurs due to

disruptions in the telomere maintenance mechanism.

Telomere damage as a result of ionizing radia-

tion-induced oxidative stress. IR causes both direct

damage to the cell macromolecules and indirect dam-

age through the water radiolysis products [28, 102].

Irradiation of water results in the formation of ROS,

reactive nitrogen species and other free radicals ca-

pable of damaging DNA and other macromolecules.

The effects of irradiation can be manifested within

several minutes to several hours after exposure. The

most reactive species are superoxide anions, hydroxyl

radicals, nitric oxide radicals, lipid radicals, and some

other molecules with a high oxidizing potential. ROS

production can also be a result of activation of some

cellular metabolic processes, as well as inflammation,

ischemia, and stress [103].

One of the most prevalent forms of oxidative

DNA damage is 8-oxo-7,8-dihydro-2′-deoxyguanosine

(8-OxodG), a product of guanine oxidation. Its accu-

mulation in DNA is considered a hallmark of chron-

ic oxidative stress [104]. Mitochondrial DNA is more

susceptible to the oxidative damage than nuclear DNA

[105, 106]. Thus, an exposure to IR induced a multi-

fold increase in the 8-OxodG content in mitochondrial

DNA [107].

Densely IR is a more potent inducer of the

long-lasting oxidative stress than sparsely IR (gam-

ma- and X-rays) [104, 108, 109]. The oxidative damage

to telomeric DNA is thought to cause premature se-

nescence by accelerating telomere shortening. Barnes

et al. [110] tested this model directly using a preci-

sion chemoptogenetic tool that generated 8-OxodG

exclusively in the telomeres. It has been shown that

a one-time induction of the 8-OxodG formation in the

telomeres was sufficient to trigger the p53-dependent

senescence. Formation of 8-OxodG activated the ATM

and ATR signaling and resulted in telomere dysfunc-

tion in replicating cells [110]. Chronic selective induc-

tion of telomeric 8-OxodG shortened the telomeres and

impaired cell proliferation over time. Accumulation

of telomeric 8-OxodG in chronically exposed 7,8-di-

hydro-8-oxoguanine-DNA glycosylase-deficient cells

triggered the replication stress, significantly increased

the loss of telomeres, and generated chromosome fu-

sions, leading to the formation of chromatin bridges

and micronuclei during cell division [111]. Targeted

oxidative stress directed toward either telomeres or

mitochondria increased the ROS production, extent of

telomere damage, mitochondrial dysfunction, and cell

apoptosis [112]. Figure 4 illustrates the relationship

between the development of disorders caused by the

elevated levels of ROS and other free radicals and de-

crease in the TA and TL.

The damage and shortening of telomeres as a re-

sult of oxidative stress development occur throughout

the lifetime of an organism against the background

of normal metabolism and influence of various dam-

aging factors and inflammation, which explains the

decrease in the TL in human peripheral blood leuko-

cytes with age [113-115]. The damaging factors causing

telomere shortening include chemotherapeutic drugs

and IR [116].

The effect of irradiation on the telomere–telo-

merase system. The IR-induced changes in the TL

depend on the type of radiation, its duration, dose

received, and time after exposure.

Analysis of TL and chromosomal instability in

the prostate cancer patients subjected to the intensi-

ty-modulated radiotherapy (IMRT) showed individual

response to the therapy: 11 patients with a relative-

ly short telomeres at baseline showed a dramatic

increase in the TL immediately post IMRT that was

sustained for at least 3 months. In patients with ini-

tially longer telomeres, the TL dramatically decreased

post IMRT [117].

The telomere–telomerase system was found to be

highly sensitive to IR. Proteins of the shelterin com-

plex play an important role in protecting telomeric

DNA from the IR-induced damage. Thus, it was shown

that the siRNA-mediated inactivation of TRF1, TRF2,

or POT1 led to the impairment of telomere protective

functions and the increase in the frequency of spon-

taneous and radiation-induced mutations in the het-

erozygous thymidine kinase locus in human lympho-

blastoid WTK1 cells after exposure to γ-radiation and

accelerated

Fe ions with an energy of 1 GeV/n at the

doses of 1 and 2 Gy. The highest increase in the muta-

tion rate was observed upon inactivation of POT1 [118].

The effect of IR on the TA varies depending on

the cell type, dose, type of radiation, and TL [118]. For

example, after exposure of human breast adenocarci-

noma MCF-7 cells to IR, the TA increased within the

first 48 h, but then decreased. These changes were

accompanied by changes in the TL. Irradiation of cul-

tured cells at a dose of 10Gy caused a decrease in the

average TL 5 days after the exposure, followed by the

partial TL recovery after 10 days [118], indicating dis-

appearance of short telomeres that had appeared af-

ter irradiation. However, it remained unclear whether

this phenomenon was caused by the actual recovery

of telomeres by telomerase or via the ALT mechanism

or by the death of cells with short telomeres.

MOSKALEVA et al.710

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Along with the decrease in the TL, the post-irra-

diation disturbances in the TA-TL system included an

increase in the proportion of senescent (β-galactosi-

dase-positive) cells to 45% (MCF-10A cells) and 70%

(MCF-7 cells) on day 10 after irradiation [118]. The

results of this detailed study suggest a high sensitivity

of the TA-TL system to the effects of IR in both normal

and tumor cells.

An increase in the TA after irradiation has been

shown in various tumor cells, such as glioma [119]

and nasopharyngeal carcinoma cells [120], colon carci-

noma and colorectal carcinoma cell lines [121], Ewing

sarcoma SK-N-MC cells, breast cancer MCF-7 cells,

chronic myelogenous leukemia K562 cells [122], etc.

The upregulation of the TA after irradiation can be

considered as a protective response leading to the in-

creased radioresistance of tumor cells. In this regard,

there is currently an active search for the efficient

and selective TA inhibitors to increase the sensitivity

of tumors to the radiation therapy.

Radiation damage to regional stem cells may be

an important mechanism in radiation-induced car-

cinogenesis and some delayed post-irradiation effects.

Stem cells are found in almost all tissues of an adult

organism. They play an important role in the main-

tenance of cellular homeostasis and post-damage tis-

sue regeneration. Since stem cells are slowly renewed

throughout the lifetime, they can accumulate genetic

damage, which can cause their malignant transforma-

tion, formation of cancer stem cells, and cancer devel-

opment, in particular, emergence of secondary tumors

after radiation therapy. Therefore, many studies of the

mechanisms of radiation carcinogenesis are currently

focused on the effects of different types of radiation

on stem cells. In addition, a decrease in the stem cells

pool due to the whole-body or regional exposure to

radiation at the doses that cause the death of some

stem cells can lead to the accelerated aging of organs

and tissues and slow down regeneration processes.

γ-Irradiation at a dose of 0.1  Gy increased the TA

in cultured mouse bone marrow mesenchymal stro-

mal cells (MSCs) 2 months after irradiation, while γ-ir-

radiation at a dose of 6  Gy and exposure to neutrons

at the doses of 0.05, 0.5, and 2  Gy decreased the TA.

At the same time, only γ-irradiation, but not exposure

to neutrons decreased the TL in the irradiated vs. con-

trol MSCs [123]. The absence of telomere shortening in

MSCs with a low TA suggests that either the existing

TA was sufficient to maintain the TL or that the cells

utilized both the TA and ALT to restore the TL.

In subsequent experiments, irradiated MSCs were

cultured for 2 months and then transplanted to mice

to induce tumors (sarcomas). Next, fibrosarcoma cell

lines were prepared from these formed tumors. In

cells of the fibrosarcoma lines, the TA was either ab-

sent (after γ-irradiation at a dose of 1  Gy and after

neutron irradiation at a dose of 0.5  Gy) or remained

at a very low level. Hence, malignant transformation

of MSCs was accompanied by the decrease in the TA

(up to its complete disappearance), which distinguish-

es sarcomas from other types of tumors, which are

characterized, on the contrary, by telomerase reacti-

vation [123].

TL was investigated as a marker of replicative

aging of bone marrow and thymus cells after pro-

longed irradiation of mice with neutrons at the doses

of 0.05-0.5  Gy  [124]. It was found that the TL in the

bone marrow cells and the thymus in control animals

aged 4 and 16 months was similar and did not change

during mice aging. In the irradiated animals, the TL

in the bone marrow and thymus did not differ from

the TL in the corresponding organs of the control

mice 2 months after exposure; however, 14 months

after the irradiation, the decrease in the TL was pro-

portional to the radiation dose in both bone marrow

and thymus cells [124]. Analysis of internal organs in

the euthanized animals found that 2 out of 10 C57Bl/6

mice had uterine tumors (squamous cell keratinizing

carcinomas) and 1 out of 10 CBA mice had uterine

carcinosarcoma. One of the CBA mice irradiated at

a dose of 50 mGy had invasive bronchoalveolar ad-

enocarcinoma in the left lung. These data attest that

neutron irradiation caused a delayed decrease in the

TL in the bone marrow and thymus and increased

the probability of tumor development. The appear-

ance of cytogenetic abnormalities in bone marrow

cells was observed at the irradiation dose of 10 mGy

and above [125].

Telomeres are more sensitive to IR than chromo-

somal DNA. Analysis of the association between the

TL and sensitivity of TK6 lymphoblasts to IR revealed

no correlation between the radiosensitivity and mean

TL; however, there was a positive correlation between

the radiosensitivity and loss of telomeres, suggesting

it is the irradiation-induced telomere loss, rather

than changes in the TL itself, that plays an important

role in the formation of radiosensitivity or radiore-

sistance [126].

Experiments in telomerase-deficient mice generat-

ed by the deletion of the telomeric RNA gene (Terc),

have shown the role of telomerase and telomeres in

the response of cells and entire organism to IR. It was

found that the telomere dysfunction in the late gen-

erations of Terc

–/–

mice has led to the development

of the increased radiosensitivity syndrome associated

with accelerated mortality, intensification of apopto-

sis in intestinal cells and thymocytes, and elevated

radiosensitivity of embryonic fibroblasts. The radio-

sensitivity of these cells correlated with a decrease

in the DDR rate, persistent chromosomal breaks, and

cytogenetic profiles characterized by complex chromo-

somal aberrations [127].

TELOMERE LENGTH AS PROGNOSTIC MARKER 711

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Fig. 4. Mechanisms of TA suppression and TL shortening in cells subjected to IR and oxidative stress. 8-OxodG, 8-oxo-7,8-di-

hydro-2′-deoxyguanosine; R-loops, RNA–DNA hybrids formed by TERRA with the cytosine-rich sequences of telomere DNA

that can cause displacement of DNA strand containing TTAGGG repeats.

DNA damage triggers the DDR response, which

causes cell cycle arrest until the damage is repaired.

The presence of unrepaired DNA damage induces per-

sistent DDR activation, leading to the cell apoptosis

and/or senescence. It is important to note that the re-

pair of DNA damage in the telomere region is limit-

ed [28,  128], which determines a higher sensitivity of

telomeres to IR compared to the rest of the genome.

The mechanisms underlying this phenomenon require

further study. Figure 4 shows the sequence of events

leading to the TA decrease and TL shortening as a

result of direct damage by IR and the action of ROS,

reactive nitrogen species, and free radicals, as well

as by the oxidative stress caused by ROS and reactive

nitrogen species generated in pathological processes

not associated with radiation.

Delayed effects of the radiation exposure on

the telomere length. The biological effects of the

long-term exposure to a low-dose IR are attributed to

the direct DNA damage and indirect effect mediated

by the oxidative changes in DNA. As specific nucleo-

protein structures with a high guanine content, telo-

meres are more sensitive to oxidative damage and

can be damaged and shortened more easily under

the combined effect of radiation and oxidative stress

caused by it.

In the study of Hiroshima atomic bomb survi-

vors, Lustig et al. [129] showed that the TL in leu-

kocytes 50 and 68 years after the exposure inversely

correlated with the radiation dose. The results indi-

cate a long-term negative effect of IR on the TL in

leukocytes, which depended on both the irradiation

dose and the age of subjects at the time of exposure

[129]. A nonlinear relationship between the TL in T

lymphocytes and radiation dose was also demonstrat-

ed in a study of 620 individuals who had survived

the atomic explosion, which discovered the presence

of longer telomeres in individuals who had received

a lower radiation dose and a trend to the TL de-

crease in subjects who had received a dose higher

than 0.5 Gy [130].

Scherthan et al. [131] examined 100 workers of

the plutonium production plant at the Mayak Produc-

tion Association, who had been chronically exposed to

plutonium-239 α-radiation and/or γ-radiation, for the

relative TL in leukocytes in comparison to the con-

trol group (51 local residents). The mean age of all

participants was about 80 years. The authors found

that the TL decreased with age. The workers irradi-

ated at the lowest dose demonstrated a significant

decrease in the TL (by ~20%) after being exposed to

external γ-radiation (≤1  Gy) or internal α-radiation

(≤0.05-0.1  Gy to red bone marrow). The relative TL

in the workers exposed to a high-dose irradiation

(>0.1  Gy for α-radiation and >1-1.5  Gy for γ-radia-

tion) did not differ from that in the control group.

MOSKALEVA et al.712

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Stratification by sex revealed a significant (~30%) de-

crease in the TL in the males exposed to the low dos-

es, but not in the females. The authors concluded that

chronic systemic exposure to different radiation doses

leads to different changes in the TL, which may be

due to the selection against cells with a low TL [131].

The TL and telomere damage were also studied

in the individuals working at the diagnostic radiolo-

gy departments and occupationally exposing to low

doses of X-ray radiation. These workers demonstrat-

ed increased levels of chromosomal aberrations and

damaged telomeres in peripheral blood lymphocytes,

as well as increased levels of lipid peroxidation prod-

ucts and 8-OxodG in the blood plasma. The latter two

parameters correlated with the extent of telomere

damage, suggesting that the chronic exposure to a

low-dose radiation causes oxidative modification of

guanine, leading to telomere damage [132].

These data confirm a delayed decrease in the TL

after exposure to a low-dose (including chronic) irra-

diation, as well as significant contribution of oxidative

stress to the telomere damage in individuals subjected

to the chronic low-dose irradiation.

Telomere length and radiosensitivity. The TL

is closely related to the cell radiosensitivity. For in-

stance, it was demonstrated that the radiosensitivi-

ty of human larynx squamous cell carcinoma Hep-2

cells negatively correlated with the TL and positively

correlated with the TA, which allowed the authors to

conclude that both TL and TA can serve as markers

for predicting the radiosensitivity of patients’ cells

[133]. These data have been confirmed in different

types of tumor cells (eight hepatocellular carcino-

ma cell lines and five breast cancer cell lines [134])

and mice [135].

A similar dependence was found for the mouse

cells defective in the telomerase gene. At the same

time, telomerase-deficient mouse fibroblasts immor-

talized by transfection with the telomerase gene dis-

played no correlation between the TL and radiosensi-

tivity (as demonstrated for three cell clones with the

TL of 13, 10, and 4  kb, respectively) [136]. The authors

concluded that the presence of TA causes stabilization

of short telomeres, which prevents the increase in the

radiosensitivity of cells.

A relationship between the TL and radiosensitiv-

ity has been well established. It was shown that the

shortening of telomeres enhances cell sensitivity to

IR, but the molecular mechanisms of this phenome-

non remain unclear. To understand the relationship

between the telomere shortening and radiation sensi-

tivity, Drissi et al. [137] showed that the late-passage

cells with short telomeres are characterized by an

increased sensitivity to IR compared to the early-pas-

sage cells with longer telomeres. Before exposure to

IR, late-passage cells had a higher baseline level of

γH2AX, which reduced after irradiation. The rates of

the appearance and disappearance of γH2AX foci in

irradiated cells decreased, indicating a reduced level

of DNA repair. Ectopic telomerase expression in the

late-passage cells completely restored the kinetics of

formation and resolution of γH2AX foci to the levels

observed in the early-passage cells. These data demon-

strate the role of TL in the DSB repair suppression in

cells with short telomeres [137].

The phosphorylation kinetics of ATM kinase and

p53 was similar in the early- and late-passage cells,

but phosphorylation of the chromatin-bound SMC1

and NBS1 proteins (ATM targets) was reduced in the

late-passage cells. The authors investigated the chro-

matin structure and showed that the late-passage chro-

matin was resistant to digestion with the micrococcal

nuclease and had a reduced level of H3K9 acetylation

and a higher level of H3K9 methylation, indicating its

transition to heterochromatin. Such chromatin con-

version to a more compact state may explain why

phosphorylation and activation of the chromatin-as-

sociated DDR proteins (H2AX, SMC1, and NBS1) were

reduced in the late-passage cells, while activation of

the non-chromatin-associated proteins (p53 and ATM)

remained unchanged. The authors concluded that

short telomeres are associated with changes in the

chromatin structure that limit the access of the acti-

vated ATM kinase to its targets present in the chroma-

tin content and restrict the DDR, which might explain

an increased radiosensitivity of cells with shortened

telomeres [137].

To study the mechanisms underlying the radiore-

sistance of tumors, Zhou etal. [138] generated a radio-

resistant cell line from the human larynx squamous

cell carcinoma Hep-2 cells. The authors showed that

the expression of some genes associated with the DNA

repair, cell cycle, apoptosis, etc. (for example, genes

for telomere proteins, such as POT1) was significant-

ly altered in the radioresistant cells, which also had

a higher TA and longer telomeres than the parental

cells. The authors concluded that both TA and TL may

be indicators of cell radioresistance [138].

Long telomeres and high TA have been commonly

associated with the radioresistance of different can-

cers. The protection of telomeres, telomere function,

and TL depend on the TA and proteins of the shel-

terin and CST complexes. Ferrandon et al. [139] eval-

uated the telomeric status of glioblastoma cells after

the photon and carbon ion irradiation and found a

significant correlation between the TL, basal POT1

expression, and photon radioresistance in  vitro. The

authors also observed a significant increase in the sur-

vival of patients with long telomeres or a high POT1

level. Expression of POT1 was a predictive indicator of

the patients’ response irrespectively of the TL. How-

ever, the observed correlations were absent in  vitro

TELOMERE LENGTH AS PROGNOSTIC MARKER 713

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

after the carbon ion irradiation. To identify radiore-

sistant tumors in patients who would benefit from the

carbon ion hadron therapy the authors proposed the

assessment of the TL and POT1 expression in tumor

biopsies [139].

As shown above, both TL and TA can be used as

markers for monitoring the patients’ condition during

radiation therapy. Indeed, it has been shown that the

stability of telomeres in peripheral blood lymphocytes

correlates with the life expectancy of patients receiv-

ing radiation therapy, and that the telomere instabili-

ty correlates with the development of toxic response

long after the radiation therapy [140]. The implemen-

tation of this approach into clinical studies will help

to analyze in more details the dynamics of this indi-

cator in patients subjected to the radiation therapy.

The increase in the radiosensitivity associated

with the TL decrease is not the only problem of cells

and organisms with short telomeres. Another conse-

quence of telomere shortening is an increased risk of

chromosome aberrations and malignant transforma-

tion of cells [82, 128, 141].

The TL stability is currently considered as a

promising marker of normal tissue radiosensitivity

that can be used for predicting the development of

complications in patients after radiation therapy [142].

The telomere–telomerase system in astronauts.

Exposure to IR is the major health risk during future

deep space missions. The keynote paper co-authored

by 38 researchers representing 33 leading aerospace

research institutes and agencies identified six process-

es that shape our current understanding of molecular

changes occurring during space missions: oxidative

stress, DNA damage, dysregulation of mitochondrial

function, epigenetic changes (including regulation of

gene activity), changes in the TL, and microbiome

modification [143].

The TL in blood cells appears to be a relevant in-

tegrative biomarker for studying the impact of space-

flight factors on astronauts, because changes in this

indicator reflect the combined effect of factors that

astronauts encounter in extreme space conditions. The

most striking discovery was the lengthening of telo-

meres during the spaceflight found in all crew mem-

bers. The TL reduced rapidly upon return to Earth, so

that eventually the crew members had significantly

shorter telomeres after the spaceflight than before it.

Chronic exposure to the space radiation and asso-

ciated development of DDR and other stress responses

may promote activation of the TL maintenance path-

ways. Although the exact mechanisms and health ef-

fects of spaceflight-associated shifts in the TL dynam-

ics remain to be elucidated, the existing findings have

already highlighted the importance of monitoring the

TL and genome stability in the cells of spacecraft crew

members for the assessment of the overall health and

risks of disease development and aging. These data

should be taken into account in the creation of per-

sonalized aerospace medicine and protective mea-

sures for future astronauts.

More detailed results of the studies of the TL in

astronauts were presented in the reports from the lab-

oratory of S.  M.  Bailey [144,  145]. The authors found

that the identical twins Scott and Mark Kelly had rela-

tively similar telomeres before the spaceflight. The telo-

meres of Mark Kelly, who stayed on Earth, remained

stable throughout the study, while the telomeres of

Scott Kelly increased in length during the spaceflight

and then shortened rapidly upon his return to Earth.

Overall, the content of short telomeres increased after

the spaceflight. The level of chromosome aberrations

also increased during the spaceflight, and the elevated

frequency of inversions persisted after the flight, indi-

cating long-term genome instability in the astronaut’s

cells after returning to Earth.

During the spaceflight, all crew members experi-

enced oxidative stress that correlated positively with

the TL dynamics. The frequency of chromosomal in-

versions increased significantly during and after the

spaceflight. The authors believed that it was an adap-

tive response of telomeres to chronic oxidative stress

under extreme conditions, because the studied cells

also demonstrated simultaneous ALT activation, as

evidenced by the increase in the chromatid exchang-

es in the telomeres. The radiation doses received by

the astronauts and calculated based on the level of

chromosome inversions were 50-350  mGy, and the

average effective dose over 6  months on the Inter-

national Space Station was 80  mSv. The authors sug-

gested that the observed damage was related to the

oxidative stress (Fig. 4) rather than to the radiation

exposure [145]. This may be true, since no changes

in the TL were found in the residents of regions with

a high natural background radiation (mean dose, 0.5

to 15  mSv/year) despite the presence of cytogenetic

abnormalities [146].

During the long-term flight, the astronauts showed

the signs of inflammation [144], which is always ac-

companied by the increase in the ROS content (oxi-

dative stress).

It should be noted that similar changes in the

TL were registered in the participants of the short-

term “Inspiration 4” civilian spaceflight, namely, an

increase in the TL during the flight and telomere

shortening after returning to Earth [147]. Other de-

tected changes had an adaptive nature.

The above data indicate the possibility of devel-

oping an adaptive response to various factors en-

countered during the spaceflight, including oxidative

stress. The detected changes in the telomeres probably

reflect a universal adaptive response to the damaging

factors.

MOSKALEVA et al.714

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

TELOMERE LENGTH AND TELOMERASE

IN TELOMEROPATHIES

There are several pathological conditions asso-

ciated with mutations in the genes involved in the

mechanisms ensuring the telomere stability. They are

accompanied by disturbances in hematopoiesis, devel-

opment of pulmonary and liver fibrosis, worsening of

nail condition, and changes in the TL. Such conditions

are called telomeropathies, or telomere biology disor-

ders [148, 149]. The TL analysis is of great importance

for the diagnostics and monitoring of telomeropathies,

while clarification of the mechanism of telomere dys-

function in such diseases is necessary for their diag-

nostics, genetic counseling, clinical management of

patients, and choice of therapy.

Dyskeratosis congenita (DC) is a congenital syn-

drome of bone marrow failure and dysplasia of oral

mucosa and skin, which is characterized by the classic

triad of nail dystrophy, spotted hyperpigmentation of

skin, and oral leukoplakia, as well as predisposition to

cancer. Genetic analysis has shown that DC is associat-

ed with a defect in the gene located in the Xq28 locus.

The DKC1 gene encodes dyskerin [150], which is one

of the proteins forming a complex with telomerase.

It is found in the nucleolus, where it binds to RNA

(including ribosomal RNA and hTERC) and influences

many cellular functions.

Laboratory diagnostics of DC is difficult. Detection

of very short telomeres in lymphocytes by flow cy-

tometry and fluorescence insitu hybridization (FISH)

in commercial laboratories can differentiate DC from

other syndromes involving bone marrow failure. Ge-

netic screening of DC patients has also revealed het-

erozygous mutations in the TERC gene, homozygous

mutations in the NOP10 and NHP2 genes coding for

proteins associated with the telomerase complex, and

mutations in the TERT gene. The autosomal dominant

form of DC is characterized by mutations in the TINF2

gene. The loss of functionally active TIN2 in the shel-

terin complex leads to the cells with extremely short

telomeres [151]. Another cause of DC is thymidylate

synthase deficiency [152]. Mutations in the CTC1,

RTEL1, ACD, PARN, NAF1, ZCCHC8, NPM1, MDM4,

RPA1, DCLRE1B, POT1, and TYMS-ENOSF1 genes were

also found in DC and DC-like diseases. These muta-

tions disrupt the functioning of telomerase and/or

proteins involved in the telomere maintenance and

lead to the appearance of short telomeres [153, 154].

Genetic testing of a large cohort of clinically di-

agnosed patients with DC and DC-like diseases has

identified several new mutations in the known genet-

ic loci, X-linked POLA1 gene, and POT1 and ZCCHC8

genes. Functional characterization of the new POLA1

and POT1 variants revealed abnormal protein–protein

interactions between primase and CST and shelterin

complex proteins, which are critical for the TL main-

tenance [155]. Assessment of the TL allows to conduct

differential diagnosis between the acquired aplastic

anemia and DC [156] and control sickle cell anemia

[157] and some other diseases of the hematopoietic

system [158]. Modern genetic technologies make it

possible to conduct such studies.

TECHNOLOGIES FOR THE ASSESSMENT

OFTELOMERASE ACTIVITY

AND TELOMERE LENGTH IN CLINICAL

AND EPIDEMIOLOGICAL STUDIES

Analysis of published data on the TA-TL system

dysfunction in the pathogenesis of diseases, including

cancer and genetic disorders associated with telo-

meropathies, has demonstrated the relevance of TA

assessment in the identification of the malignant na-

ture of a tumor. The presence of short telomeres can

be an important disease (telomeropathy) marker, an

indicator of individual sensitivity to the damaging fac-

tors, and a prognostic marker for the development of

complications during chemo- and radiation therapy of

oncological diseases. The significance of disease diag-

nostics and monitoring has promoted the development

of methods for the assessment of TA and TL in clinical

and epidemiological studies.

The methods for measuring TA in cell and tissue

extracts were described in detail in the review [159].

The authors examined the sensitivity, advantages, dis-

advantages, and implementation of existing methods

for TA analysis, which they divided into two types:

direct assessment of telomerase-synthesized DNA and

methods using various signal amplification schemes to

increase the sensitivity. There are numerous ongoing

studies on the improvement of TA analysis methods

[87, 160, 161].

In terms of sensitivity, cost, complexity of imple-

mentation, and equipment availability, the most avail-

able method for the TA assessment in tumor tissue

in clinical trials is amplification of telomeric repeats

followed by their fluorescent detection, called TRAP

(telomeric repeat amplification protocol). The method

is based on the elongation of oligonucleotide substrate

by telomerase, PCR amplification of the synthesized

telomeric repeats, separation of the amplified TRAP

products by electrophoresis, their visualization by

staining with the SYBR Gold dye, and gel documen-

tation for subsequent processing of the results and

evaluation of the relative TA vs. positive control sam-

ple [162]. An optimized protocol for this method was

described in [163] that included a procedure for pre-

paring the lysate from surgical specimens, as well as

the protocol for the result analysis and quantification

suitable for the use in diagnostic studies.

TELOMERE LENGTH AS PROGNOSTIC MARKER 715

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

Given the above-mentioned difficulties associated

with the standardization of sample preparation, it is

possible that the TA assessment in biological materials

will be eventually replaced by the analysis of C228T

and C250T mutations in the hTERT gene promoter or

other mutations that lead to the telomerase activation

and malignant transformation [89]. A combination of

modern DNA sequencing technologies used for the

mutation identification and liquid or conventional bi-

opsy might be a more promising approach compared

to the routine TA assessment.

A wide range of methods have been developed

for the TL assessment, including analysis of terminal

restriction fragments (TRFs), quantitative PCR (qPCR),

STELA (single telomere length analysis), MMQPCR

(monochrome multiplex qPCR), Q-FISH (quantitative

FISH of telomeres in metaphase chromosomes), and

FlowFISH (determination of relative TL using flow cy-

tofluorimetry). Until recently, FlowFISH had been the

only method acceptable for clinical use, as it allows

highly reproducible, simple, and rapid measurement

of absolute TL [164]. The authors of [164] developed

an algorithm for converting the flow cytometry data

into the absolute TL expressed in kb, which makes

it possible to compare results obtained in different

laboratories, as well as to perform the retrospective

conversion of previously obtained flow cytometry

data. Flow-FISH and qPCR offer specific and highly

sensitive measurement of normal-length telomeres.

However, the sensitivity and specificity of qPCR in the

detection of short telomeres are lower [165], although

this method is suitable for TL measurement in epide-

miological studies. The STELA method has the high-

est sensitivity for analyzing short telomeres, based on

the fact that all telomeres have the GGG repeat at the

3′ end. This method has also been adapted for epide-

miological studies, but it requires special equipment

and reagents [166].

Hence, this brief review of methods used for TA

and TL analysis allows us to conclude that the current

array of molecular biological and genetic technologies

allows to conduct research on the TA and TL in clinical

and epidemiological studies, although these methods

and software for data processing continue to improve.

CONCLUSION

Analysis of published data on the telomere biol-

ogy and mechanisms of TL maintenance in human

cells demonstrate that these topics still remain in the

research focus. In recent years, new data have been

obtained on the important role of CST–Polα/Prim in

the TL maintenance. The primase forms a complex

with CST, which ensures the high specificity of repli-

cation initiation for the complementary C-strand after

completion of the G-chain synthesis by telomerase. In

the case of low TA or its absence, the TL is maintained

by the ALT mechanism based on homologous recom-

bination. The regulation of TA by different mecha-

nisms has been well studied, including the control of

TA at the epigenetic level. TERRA, a long non-coding

telomeric repeat-containing RNA transcribed by RNA

polymerase II from the intrachromosomal telomeric

repeats, likely plays an important role in telomerase

regulation and heterochromatin organization in the

telomere region.

TL is an important marker of cells well-being.

The state of telomeres (length, structure, presence of

oxidized guanine and/or G4s, quality of shelterin and

CST complex proteins) is currently considered as an

indicator of health. The accumulation of short telo-

meres indicates replicative aging of proliferating cells,

transition to the senescent state, and increased sen-

sitivity to damaging factors. Proteins of the shelterin

complex are crucial for the telomere protection. The

inactivation of shelterin binding to the telomere DNA

leads to the appearance of unprotected telomeres,

activation of different DDR pathways, and genomic

instability. The alternative functions of telomerase

associated with the anti-apoptotic activity of its com-

ponents after their translocation to the nucleus (TR)

or mitochondria (TERT) may be of great importance

in the maintenance of cell stability.

A high TA can serve as a marker of neoplasm

malignancy. Mutations in genes coding for proteins

involved in the maintenance of telomere structure

and length lead to the development of genetic dis-

eases (telomeropathies) that can be diagnosed by the

analysis of TL and TA.

IR damages telomeres via direct DNA damage and

through the action of ROS generated by the radiolysis

of intracellular water. A high guanine content makes

telomeres highly sensitive to ROS, while formation

of 8-OxodG in the telomere DNA inhibits telomerase.

Similar lesions were detected after the long-term γ-

and X-irradiation at low doses (mainly after a certain

period of time) or after the chronic low-dose irradia-

tion of occupationally exposed individuals.

According to the National Aeronautics and Space

Administration, changes in the TL in astronauts rep-

resent one of the important biological responses to

the effects of spaceflight factors. Both TL and TA are

among the parameters that should be analyzed in as-

tronauts before, during, and after completion of space

mission.

Telomeres are dynamic structures that undergo

significant changes under the influence of deleterious

factors. The TL is determined by the cumulative im-

pact of all endogenous and exogenous damaging fac-

tors acting throughout the lifetime, rather than by the

chronological age.

MOSKALEVA et al.716

BIOCHEMISTRY (Moscow) Vol. 90 No. 6 2025

The current state of biochemical and molecular

genetic methods has made it possible to develop tech-

nologies for the TA assay and identification of muta-

tions affecting TA that can be used for the diagnostics

of malignant neoplasms, as well as the methods for

TL assessment in order to monitor telomeropathies

and health status in clinical practice. The introduction

of these technologies into clinical practice and epide-

miological studies will significantly expand the pos-

sibilities of medical and biological diagnostic studies,

allow prediction of individual sensitivity of patients

to the planned radiation and chemotherapeutic treat-

ment, and facilitate the assessment of risks of devel-

oping unwanted late complications.

Abbreviations. 8-OxodG, 8-oxo-7,8-dihydro-2′-de-

oxyguanosine; ALT, alternative lengthening of telo-

meres; CST–Polα/Prim, CST–Polymerase α/primase;

DC, dyskeratosis congenita; DDR, DNA damage re-

sponse; DSB, DNA double-strand break; G4s, G-qua-

druplexes; TERT, telomerase reverse transcriptase; TR

(TERC), telomerase RNA component; IR, ionizing radi-

ation; MSC, mesenchymal stromal cell; ROS, reactive

oxygen species; TA, telomerase activity; TL, telomere

length.

Contributions. E.Yu.M. and A.I.G developed the

review concept and wrote the “Introduction” and

“Conclusion” sections; A.S.Zh., O.V.V., and S.A.V. re-

trieved the published information; E.Yu.M., A.I.G.,

and S.A.V. wrote the section “Telomere structure

and mechanisms of telomere maintenance”; E.Yu.M.,

A.S.Zh., and O.V.V. wrote the section “Telomere sensi-

tivity to ionizing radiation”; E.Yu.M. wrote the section

“Telomere length and telomerase in telomeropathies”;

A.I.G. and O.V.V wrote the section “Technologies for the

assessment of telomerase activity and telomere length

in clinical and epidemiological studies”. All authors re-

viewed and edited the manuscript.

Funding. The work was carried out within the

State Assignment for the National Research Center

“Kurchatov Institute”.

Ethics approval and consent to participate.

This work does not contain any studies involving hu-

man and animal subjects.

Conflict of interest. The authors of this work de-

clare that they have no conflicts of interest.

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