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Nat Genet. 2019 Jan;51(1):36-41. doi: 10.1038/s41588-018-0285-7. Epub 2018 Dec 3.

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

Author information

1
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
3
Institute for Information Transmission Problems (Kharkevich Institute), Russian Academy of Sciences, Moscow, Russia.
4
Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
5
Science for Life Laboratory, Department of Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
6
Skolkovo Institute of Science and Technology, Skolkovo, Russia.
7
Inserm U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France.
8
Department of Dermatology and Venereology, Université Paris 7, St. Louis Hospital, Paris, France.
9
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
10
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
11
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ssunyaev@rics.bwh.harvard.edu.
12
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. ssunyaev@rics.bwh.harvard.edu.

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.

PMID:
30510240
PMCID:
PMC6317876
DOI:
10.1038/s41588-018-0285-7
[Indexed for MEDLINE]
Free PMC Article

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