Dysfunction of Lamin B and Physiological Aging Cause Telomere Instability in Drosophila Germline

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Valeriya V. Morgunova^1#, Olesya A. Sokolova^1#, Tatyana V. Sizova¹, Leonid G. Malaev^1,2, Dmitry S. Babaev^1,2, Dmitry A. Kwon³, and Alla I. Kalmykova^1,a*

¹Institute of Molecular Genetics of National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia

²Faculty of Biotechnology, Lomonosov Moscow State University, 119991 Moscow, Russia

³Kurchatov Center for Genome Research, National Research Centre “Kurchatov Institute”, 123182 Moscow, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to this study.

Received September 12, 2022; Revised October 31, 2022; Accepted November 14, 2022

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Chromatin spatial organization in the nucleus is essential for the genome functioning and regulation of gene activity. The nuclear lamina and lamina-associated proteins, lamins, play a key role in this process. Lamin dysfunction leads to the decompaction and transcriptional activation of heterochromatin, which is associated with the premature aging syndrome. In many cell types, telomeres are located at the nuclear periphery, where their replication and stability are ensured by the nuclear lamina. Moreover, diseases associated with defects in lamins and telomeres have similar manifestations and resemble physiological aging. Understanding molecular changes associated with aging at the organismal level is especially important. In this study, we compared the effects caused by the mutation in lamin B and physiological aging in the germline of the model organism Drosophila melanogaster. We have shown that the impaired localization of lamin B leads to the heterochromatin decompaction and transcriptional activation of some transposable elements and telomeric repeats. Both DNA damage and activation of homologous recombination in the telomeres were observed in the germ cells of lamin B mutants. The instability of repeat-enriched heterochromatin can be directly related to the genome destabilization, germ cell death, and sterility observed in lamin B mutants. Similar processes were observed in Drosophila germline in the course of physiological aging, which indicates a close link between the maintenance of the heterochromatin stability at the nuclear periphery and mechanisms of aging.

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KEY WORDS: lamin B, telomeres, aging, germline, heterochromatin, retrotransposons, transcription, recombination, Rad51, γH2Av, Drosophila

DOI: 10.1134/S000629792212015X

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