The Development of Genetic Toxicology within the Context of M. E. Lobashev's Phisiological Hypothesis of the Mutation Process
- Authors: Stepchenkova E.I.1,2, Zhuk A.S.1,2,3, Shumega A.R.1,2, Devyatkin D.M.2, Andreychuk Y.V.1,2, Shipunova A.E.2, Kravtsova E.V.1,2, Zotova I.V.1,2, Tarakhovskaya E.R.1,2, Inge-Vechtomov S.G.1,2
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Affiliations:
- Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch
- Saint Petersburg State University
- Institute of Applied Computer Science, ITMO University
- Issue: Vol 61, No 11 (2025)
- Pages: 71–84
- Section: ОБЩИЕ ВОПРОСЫ И ТЕХНОЛОГИИ
- URL: https://ogarev-online.ru/0016-6758/article/view/361186
- DOI: https://doi.org/10.7868/S3034510325110081
- ID: 361186
Cite item
Abstract
Keywords
About the authors
E. I. Stepchenkova
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State University
Email: stepchenkova@gmail.com
St. Petersburg, Russia
A. S. Zhuk
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State University; Institute of Applied Computer Science, ITMO UniversitySt. Petersburg, Russia; St. Petersburg, Russia
A. R. Shumega
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
D. M. Devyatkin
Saint Petersburg State UniversitySt. Petersburg, Russia
Yu. V. Andreychuk
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
A. E. Shipunova
Saint Petersburg State UniversitySt. Petersburg, Russia
E. V. Kravtsova
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
I. V. Zotova
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
E. R. Tarakhovskaya
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
S. G. Inge-Vechtomov
Vavilov Institute of General Genetics, Russian Academy of Sciences, St. Petersburg Branch; Saint Petersburg State UniversitySt. Petersburg, Russia
References
- MacGregor J.T., Casciano D., Muller L. Strategies and testing methods for identifying mutagenic risks // Mutat. Res. 2000. V. 455. № 1–2. P. 3–20. https://doi.org/.1016/s0027-5107(00)00116-0
- Дурнев А.Д., Жанатаев А.К. Актуальные аспекты генетической токсикологии лекарственных средств // Ведомости Науч. центра экспертизы средств мед. применения. Регуляторные исследования и экспертиза лекарственных средств. 2022. Т. 12. № 1. С. 90–109. https://doi.org/.30895/1991-2919-2022-12-1-90-109
- Dearfield K.L., Cimino M.C., McCarroll N.E. et al. Genotoxicity risk assessment: A proposed classification strategy // Mutat. Res. 2002. V. 521. № 1–2. P. 121–135. https://doi.org/10.1016/s1383-5718(02)00236-x
- Zhuk A.S., Stepchenkova E.I., Inge-Vechtomov S.G. M.E. Lobashev’s physiological theory of the mutation process and the formation of contemporary views on mutational changes in genetic material // Ecol. Genet. 2024. V. 21. № 4. P. 329–342. https://doi.org/.17816/ecogen623886
- Abdulovic A., Kim N., Jinks-Robertson S. Mutagenesis and the three R's in yeast // DNA Repair (Amsterdam). 2006. V. 5. № 4. P. 409–421. https://doi.org/.1016/j.dnarep.2005.11.006
- Waisertreiger I.S., Liston V.G., Menezes M.R. et al. Modulation of mutagenesis in eukaryotes by DNA replication fork dynamics and quality of nucleotide pools // Environ. Mol. Mutagen. 2012. V. 53. № 9. P. 699–724. https://doi.org/.1002/em.21735
- Hao Q., Li J., Yeap L.S. Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation // Sci. China Life Sci. 2024. V. 67. № 11. P. 2344–2353. https://doi.org/.1007/s11427-024-2615-1
- Acuna-Hidalgo R., Veltman J.A., Hoischen A. New insights into the generation and role of de novo mutations in health and disease // Genome Biol. 2016. V. 17. № 1. P. 241. https://doi.org/.1186/s13059-016-1110-1
- Инге-Вечтомов С.Г., Голубкова Е.В., Журавлева Г.А. Первая университетская школа российской генетики // Генетика. 2023. Т. 59. № 5. C. 606–610. https://doi.org/.31857/s0016675823050077
- Лобашев М.Е. О природе действия внешних условий на динамику мутационного процесса: Тез. дис. … докт. биол. наук. Л.: Лен. ун-ет, 1946. 3 с.
- Лобашев М.Е. Физиологическая (паранекротическая) гипотеза мутационного процесса // Вестник Ленингр. ун-та. 1947. № 8. C. 10–29.
- Nemeth E., Szuts D. The mutagenic consequences of defective DNA repair // DNA Repair (Amsterdam). 2024. V. 139. https://doi.org/.1016/j.dnarep.2024.103694
- Klaasen S.J., Kops G. Chromosome inequality: Causes and consequences of non-random segregation errors in mitosis and meiosis // Cells. 2022. V. 11. № 22. P. 3564. https://doi.org/.3390/cells11223564
- Friedberg E.C., Walker G.C., Siede W. et al. DNA Repair and Mutagenesis. 2nd Ed. Washington, D.C.: ASM Press, 2006.
- Maron D.M., Ames B.N. Revised methods for the Salmonella mutagenicity test // Mut. Res. 1983. V. 113. № 3–4. P. 173–215. https://doi.org/.1016/0165-1161(83)90010-9
- Миронов А.Н. Руководство по проведению доклинических исследований лекарственных средств. Ч. 1. М.: Гриф и К, 2012. 944 с.
- Martin L.J. DNA damage and repair: Relevance to mechanisms of neurodegeneration // J. Neuropath. Exp. Neurol. 2008. V. 67. № 5. P. 377–387. https://doi.org/.1097/NEN.0b013e31816ff780
- Yeeles J.T., Poli J., Marians K.J., Pasero P. Rescuing stalled or damaged replication forks // Cold Spring Harb. Perspect. Biol. 2013. V. 5. № 5. https://doi.org/.1101/cshperspect.a012815
- Calkins A.S., Iglehart J.D., Lazaro J.B. DNA damage-induced inhibition of rRNA synthesis by DNA-PK and PARP-1 // Nucl. Acids Res. 2013. V. 41. № 15. P. 7378–7386. https://doi.org/10.1093/nar/gkt502
- Zhuk A.S., Shiriaeva A.A., Andreychuk Y.V. et al. Detection of primary DNA lesions by transient changes in mating behavior in yeast Saccharomyces cerevisiae using the alpha-test // Int. J. Mol. Sci. 2023. V. 24. № 15. https://doi.org/10.3390/ijms241512163
- Bregeon D., Doddridge Z.A., You H.J. et al. Transcriptional mutagenesis induced by uracil and 8-oxoguanine in Escherichia coli // Mol. Cell. 2003. V. 12. № 4. P. 959–970. https://doi.org/10.1016/s1097-2765(03)00360-5
- Bregeon D., Peignon P.A., Sarasin A. Transcriptional mutagenesis induced by 8-oxoguanine in mammalian cells // PLoS Genet. 2009. V. 5. № 7. https://doi.org/10.1371/journal.pgen.1000577
- Olive P.L., Banath J.P. The comet assay: А method to measure DNA damage in individual cells // Nat Protoc. 2006. V. 1. № 1. P. 23–29. https://doi.org/10.1038/nprot.2006.5
- Sharma A., Singh K., Almasan A. Histone H2AX phosphorylation: A marker for DNA damage // Methods Mol. Biol. 2012. V. 920. P. 613–626. https://doi.org/10.1007/978-1-61779-998-3_40
- Fenech M. The micronucleus assay determination of chromosomal level DNA damage // Methods Mol. Biol. 2008. V. 410. P. 185–216. https://doi.org/10.1007/978-1-59745-548-0_12
- Jeggo P.A. The fidelity of repair of radiation damage // Radiat Prot. Dosimetry. 2002. V. 99. № 1–4. P. 117–122. https://doi.org/10.1093/oxfordjournals.rpd.a006740
- Lujan S.A., Williams J.S., Kunkel T.A. DNA polymerases divide the labor of genome replication // Trends Cell Biol. 2016. V. 26. № 9. P. 640–654. https://doi.org/10.1016/j.tcb.2016.04.012
- Pavlov Y.I., Zhuk A.S., Stepchenkova E.I. DNA polymerases at the eukaryotic replication fork thirty years after: connection to cancer // Cancers (Basel). 2020. V. 12. № 12. https://doi.org/10.3390/cancers12123489
- Johnson A., O'Donnell M. Cellular DNA replicases: Сomponents and dynamics at the replication fork // Annu. Rev. Biochem. 2005. V. 74. P. 283–315. https://doi.org/10.1146/annurev.biochem.73.011303.073859
- Kochenova O.V., Soshkina J.V., Stepchenkova E.I. et al. Participation of translesion synthesis DNA polymerases in the maintenance of chromosome integrity in yeast Saccharomyces cerevisiae // Biochemistry (Moscow). 2011. V. 76. № 1. P. 49–60. https://doi.org/10.1134/s000629791101007x
- Kochenova O.V., Bezalel-Buch R., Tran P. et al. Yeast DNA polymerase zeta maintains consistent activity and mutagenicity across a wide range of physiological dNTP concentrations // Nucl. Acids Res. 2017. V. 45. № 3. P. 1200–1218. https://doi.org/10.1093/nar/gkw1149
- Northam M.R., Robinson H.A., Kochenova O.V. et al. Participation of DNA polymerase zeta in replication of undamaged DNA in Saccharomyces cerevisiae // Genetics. 2010. V. 184. № 1. P. 27–42. https://doi.org/10.1534/genetics.109.107482
- Stepchenkova E.I., Tarakhovskaya E.R., Siebler H.M. et al. Defect of Fe-S cluster binding by DNA polymerase delta in yeast suppresses UV-induced mutagenesis, but enhances DNA polymerase zeta – dependent spontaneous mutagenesis // DNA Repair (Amsterdam). 2017. V. 49. P. 60–69. https://doi.org/10.1016/j.dnarep.2016.11.004
- Инге-Вечтомов С.Г. Матричный принцип в биологии (прошлое, настоящее, будущее?) // Экол. генетика. 2003. Т. 1. № 1. С. 6–15. https://doi.org/10.17816/ecogen106-15
- Дурнев А.Д., Жанатаев А.К., Шредер О.В., Середенина В.С. Генотоксические поражения и болезни // Мол. медицина. 2013. № 3. С. 3–19.
- Matos-Rodrigues G., Hisey J.A., Nussenzweig A., Mirkin S.M. Detection of alternative DNA structures and its implications for human disease // Mol. Cell. 2023. V. 83. № 20. P. 3622–3641. https://doi.org/10.1016/j.molcel.2023.08.018
- Northam M.R., Moore E.A., Mertz T.M. et al. DNA polymerases zeta and Rev1 mediate error-prone bypass of non-B DNA structures // Nucl. Acids Res. 2014. V. 42. № 1. P. 290–306. https://doi.org/10.1093/nar/gkt830
- Zhuk A.S., Stepchenkova E.I., Zotova I.V. et al. G-quadruplex forming DNA sequence context is enriched around points of somatic mutations in a subset of multiple myeloma patients // Int. J. Mol. Sci. 2024. V. 25. № 10. https://doi.org/10.3390/ijms25105269
- Rajan-Babu I.S., Dolzhenko E., Eberle M.A., Friedman J.M. Sequence composition changes in short tandem repeats: Heterogeneity, detection, mechanisms and clinical implications // Nat. Rev. Genet. 2024. V. 25. № 7. P. 476–499. https://doi.org/10.1038/s41576-024-00696-z
- Landre T., Des Guetz G. Microsatellite instability-high status as a pan-cancer biomarker for immunotherapy efficacy // Cancer Immunol. Immunother. 2025. V. 74. № 4. P. 122. https://doi.org/10.1007/s00262-025-03980-x
- Aksenova A.Y., Zhuk A.S., Lada A.G. et al. Genome instability in multiple myeloma: facts and factors // Cancers (Basel). 2021. V. 13. № 23. https://doi.org/10.3390/cancers13235949
- Dabin J., Giacomini G., Petit E., Polo S.E. New facets in the chromatin-based regulation of genome maintenance // DNA Repair (Amst.). 2024. V. 140. https://doi.org/10.1016/j.dnarep.2024.103702
- Андрейчук Ю.В., Задорский С.П., Жук А.С. и др. Связь матричных процессов I и II рода: амилоиды и стабильность генома // Мол. биология. 2020. Т. 54. № 5. С.750–775. https://doi.org/10.31857/s002689842005002x
- Zotova I., Stepchenkova E., Pavlov Y. Contribution of cytosine desaminases of AID/APOBEC family to carcinogenesis // Biol. Commun. 2019. V. 64. № 2. P. 110–123. https://doi.org/10.21638/spbu03.2019.203
- Kciuk M., Bukowski K., Marciniak B., Kontek R. Advances in DNA repair-emerging players in the arena of eukaryotic DNA repair // Int. J. Mol. Sci. 2020. V. 21. № 11. https://doi.org/10.3390/ijms21113934
- Phipps J., Dubrana K. DNA repair in space and time: Safeguarding the genome with the cohesin complex // Genes. 2022. V. 13. № 2. https://doi.org/10.3390/genes13020198
- Rembovskiy V.R., Mogilenkova L.A. Personalized toxicology: Phenomenology, relevance, development prospects // Med. Acad. J. 2020. V. 20. № 3. P. 61–73. https://doi.org/10.17816/maj34959
- Li T., Yang Y., Qi H. et al. CRISPR/Cas9 therapeutics: Progress and prospects // Signal Transduct. Target. Ther. 2023. V. 8. № 1. P. 36. https://doi.org/10.1038/s41392-023-01309-7
- Jinek M., Chylinski K., Fonfara I. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity // Science. 2012. V. 337. № 6096. P. 816–821. https://doi.org/10.1126/science.1225829
- Geisinger J.M., Turan S., Hernandez S. et al. In vivo blunt-end cloning through CRISPR/Cas9-facilitated non-homologous end-joining // Nucl. Acids Res. 2016. V. 44. № 8. P. e76. https://doi.org/10.1093/nar/gkv1542
- Chu V.T., Weber T., Wefers B. et al. Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells // Nat. Biotechnol. 2015. V. 33. № 5. P. 543–548. https://doi.org/10.1038/nbt.3198
- Zhang N., Roberts H.M., Van Eck J., Martin G.B. Generation and molecular characterization of CRISPR/ Cas9-induced mutations in 63 immunity-associated genes in tomato reveals specificity and a range of gene modifications // Front. Plant Sci. 2020. V. 11. https://doi.org/10.3389/fpls.2020.00010
- Tang X., Liu G., Zhou J. et al. A large-scale whole-genome sequencing analysis reveals highly specific genome editing by both Cas9 and Cpf1 (Cas12a) nucleases in rice // Genome Biol. 2018. V. 19. № 1. P. 84. https://doi.org/10.1186/s13059-018-1458-5
- Gallagher D.N., Haber J.E. Repair of a site-specific DNA cleavage: Old-school lessons for Cas9-mediated gene editing // ACS Chem. Biol. 2018. V. 13. № 2. P. 397–405. https://doi.org/10.1021/acschembio.7b00760
- Hwang G.H., Yu J., Yang S. et al. CRISPR-sub: Analysis of DNA substitution mutations caused by CRISPR-Cas9 in human cells // Comput. Struct. Biotechnol. J. 2020. V. 18. P. 1686–1694. https://doi.org/10.1016/j.csbj.2020.06.026
- Kosicki M., Tomberg K., Bradley A. Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements // Nat. Biotechnol. 2018. V. 36. № 8. P. 765–771. https://doi.org/10.1038/nbt.4192
- Daer R.M., Cutts J.P., Brafman D.A. et al. The impact of chromatin dynamics on Cas9-mediated genome editing in human cells // ACS Synth. Biol. 2017. V. 6. № 3. P. 428–438. https://doi.org/10.1021/acssynbio.5b00299
- Pattanayak V., Lin S., Guilinger J.P. et al. High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity // Nat. Biotechnol. 2013. V. 31. № 9. P. 839–843. https://doi.org/10.1038/nbt.2673
- Corsi G.I., Qu K., Alkan F. et al. CRISPR/Cas9 gRNA activity depends on free energy changes and on the target PAM context // Nat. Commun. 2022. V. 13. № 1. P. 3006. https://doi.org/10.1038/s41467-022-30515-0
- Yang D., Scavuzzo M.A., Chmielowiec J. et al. Enrichment of G2/M cell cycle phase in human pluripotent stem cells enhances HDR-mediated gene repair with customizable endonucleases // Sci. Rep. 2016. V. 6. https://doi.org/10.1038/srep21264
- Kleinstiver B.P., Pattanayak V., Prew M.S. et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects // Nature. 2016. V. 529. № 7587. P. 490–495. https://doi.org/10.1038/nature16526
- Rozners E. Chemical modifications of CRISPR RNAs to improve gene-editing activity and specificity // J. Am. Chem. Soc. 2022. V. 144. № 28. P. 12584–12594. https://doi.org/10.1021/jacs.2c02633
- Lohia A., Sahel D.K., Salman M. et al. Delivery strategies for CRISPR/Cas genome editing tool for retinal dystrophies: challenges and opportunities // Asian J. Pharm. Sci. 2022. V. 17. № 2. P. 153–176. https://doi.org/10.1016/j.ajps.2022.02.001
- Shumega A.R., Pavlov Y.I., Chirinskaite A.V. et al. CRISPR/Cas9 as a mutagenic factor // Int. J. Mol. Sci. 2024. V. 25. № 2. https://doi.org/10.3390/ijms25020823
- Mišík M., Nersesyan A., Ferk F. et al. Search for the optimal genotoxicity assay for routine testing of chemicals: Sensitivity and specificity of conventional and new test systems // Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2022. V. 881. https://doi.org/10.1016/j.mrgentox.2022.503524
- Satam H., Joshi K., Mangrolia U. et al. Next-generation sequencing technology: current trends and advancements // Biology (Basel). 2023. V. 12. № 7. https://doi.org/10.3390/biology12070997
- Kucab J.E., Zou X., Morganella S. et al. A compendium of mutational signatures of environmental agents // Cell. 2019. V. 177. № 4. P. 821–836. e16. https://doi.org/10.1016/j.cell.2019.03.001
- Zou X., Koh G.C.C., Nanda A.S. et al. A systematic CRISPR screen defines mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage // Nat. Cancer. 2021. V. 2. № 6. P. 643–657. https://doi.org/10.1038/s43018-021-00200-0
- Kandoth C., McLellan M.D., Vandin F. et al. Mutational landscape and significance across 12 major cancer types // Nature. 2013. V. 502. № 7471. P. 333–339. https://doi.org/10.1038/nature12634
- Alexandrov L.B., Nik-Zainal S., Wedge D.C. et al. Signatures of mutational processes in human cancer // Nature. 2013. V. 500. № 7463. P. 415–421. https://doi.org/10.1038/nature12477
- Alexandrov L.B., Kim J., Haradhvala N.J. et al. The repertoire of mutational signatures in human cancer // Nature. 2020. V. 578. № 7793. P. 94–101. https://doi.org/10.1038/s41586-020-1943-3
- Lada A.G., Stepchenkova E.I., Waisertreiger I.S. et al. Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase // PLoS Genet. 2013. V. 9. № 9. https://doi.org/10.1371/journal.pgen.1003736
- Budczies J., Kazdal D., Menzel M. et al. Tumour mutational burden: Сlinical utility, challenges and emerging improvements // Nat. Rev. Clin. Oncol. 2024. V. 21. № 10. P. 725–742. https://doi.org/10.1038/s41571-024-00932-9
- Osipov A., Lim S.J., Popovic A. et al. Tumor mutational burden, toxicity, and response of immune checkpoint inhibitors targeting PD(L)1, CTLA-4, and combination: A meta-regression analysis // Clin. Cancer Res. 2020. V. 26. № 18. P. 4842–4851. https://doi.org/10.1158/1078-0432.ccr-20-0458
- Kashima Y., Sakamoto Y., Kaneko K. et al. Single-cell sequencing techniques from individual to multiomics analyses // Exp. Mol. Med. 2020. V. 52. № 9. P. 1419–1427. https://doi.org/10.1038/s12276-020-00499-2
- Жук А.С., Кострома И.И., Степченкова Е.И. и др. Мутационный профиль генома нормальных и опухолевых клеток у больного множественной миеломой (клиническое наблюдение) // Клин. онкогематология. 2024. V. 16. № 3. https://doi.org/10.21320/2500-2139-2023-16-3-337-349
- Cho E., Swartz C.D., Williams A. et al. Error-corrected duplex sequencing enables direct detection and quantification of mutations in human TK6 cells with strong inter-laboratory consistency // Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2023. V. 889. https://doi.org/10.1016/j.mrgentox.2023.503649
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