Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations

Vladimir B. Seplyarskiy, Evgeny E. Akkuratov, Natalia Akkuratova, Maria A. Andrianova, Sergey I. Nikolaev, Georgii A. Bazykin, Igor Adameyko, Shamil R. Sunyaev

Research output

3 Citations (Scopus)

Abstract

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.

Original languageEnglish
Pages (from-to)36-41
Number of pages8
JournalNature Genetics
Volume51
Issue number1
DOIs
Publication statusPublished - Jan 2019

Scopus subject areas

  • Genetics

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    Seplyarskiy, V. B., Akkuratov, E. E., Akkuratova, N., Andrianova, M. A., Nikolaev, S. I., Bazykin, G. A., Adameyko, I., & Sunyaev, S. R. (2019). Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations. Nature Genetics, 51(1), 36-41. https://doi.org/10.1038/s41588-018-0285-7