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

TitleError-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations.
Publication TypeJournal Article
Year of Publication2019
AuthorsSeplyarskiy, VB, Akkuratov, EE, Akkuratova, N, Andrianova, MA, Nikolaev, SI, Bazykin, GA, Adameyko, I, Sunyaev, SR
JournalNat Genet
Volume51
Issue1
Pagination36-41
Date Published2019 Jan
ISSN1546-1718
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.

DOI10.1038/s41588-018-0285-7
Alternate JournalNat. Genet.
PubMed ID30510240
PubMed Central IDPMC6317876
Grant ListR01 MH101244 / MH / NIMH NIH HHS / United States
R35 GM127131 / GM / NIGMS NIH HHS / United States
U01 HG009088 / HG / NHGRI NIH HHS / United States