Inhibitory Effects of 7-Methylguanine and Its Metabolite 8-Hydroxy-7-Methylguanine on Human Poly(ADP-Ribose) Polymerase 1

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Tatyana A. Kurgina^1#, Stanislav I. Shram^2#, Mikhail M. Kutuzov¹, Tatyana V. Abramova¹, Tatyana A. Shcherbakova³, Ekaterina A. Maltseva¹, Vladimir V. Poroikov⁴, Olga I. Lavrik^1,5, Vytas K. Švedas^6,7, and Dmitry K. Nilov^3,a*

¹Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Siberian Branch, 630090 Novosibirsk, Russia

²Institute of Molecular Genetics of National Research Center “Kurchatov Institute”, 123182 Moscow, Russia

³Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

⁴Institute of Biomedical Chemistry, 119121 Moscow, Russia

⁵Novosibirsk State University, 630090 Novosibirsk, Russia

⁶Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

⁷Research Computing Center, Lomonosov Moscow State University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to this study.

Received April 22, 2022; Revised May 23, 2022; Accepted May 23, 2022

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Previously, we have found that a nucleic acid metabolite, 7-methylguanine (7mGua), produced in the body can have an inhibitory effect on the poly(ADP-ribose) polymerase 1 (PARP1) enzyme, an important pharmacological target in anticancer therapy. In this work, using an original method of analysis of PARP1 activity based on monitoring fluorescence anisotropy, we studied inhibitory properties of 7mGua and its metabolite, 8-hydroxy-7-methylguanine (8h7mGua). Both compounds inhibited PARP1 enzymatic activity in a dose-dependent manner, however, 8h7mGua was shown to be a stronger inhibitor. The IC₅₀ values for 8h7mGua at different concentrations of the NAD⁺ substrate were found to be 4 times lower, on average, than those for 7mGua. The more efficient binding of 8h7mGua in the PARP1 active site is explained by the presence of an additional hydrogen bond with the Glu988 catalytic residue. Experimental and computational studies did not reveal the effect of 7mGua and 8h7mGua on the activity of other DNA repair enzymes, indicating selectivity of their inhibitory action.

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KEY WORDS: poly(ADP-ribose) polymerase, DNA repair, inhibitor, 7-methylguanine, 8-hydroxy-7-methylguanine

DOI: 10.1134/S0006297922080132

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