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Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations
Harvard Med Sch, Brigham & Womens Hosp, Div Genet, Boston, MA USA.;Harvard Med Sch, Dept Biomed Informat, Boston, MA USA.;Russian Acad Sci, Inst Informat Transmiss Problems, Kharkevich Inst, Moscow, Russia..
KTH, School of Engineering Sciences (SCI), Applied Physics, Biophysics. KTH, Centres, Science for Life Laboratory, SciLifeLab. St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia.;Royal Inst Technol, Dept Appl Phys, Sci Life Lab, Stockholm, Sweden..
St Petersburg State Univ, Inst Translat Biomed, St Petersburg, Russia..
Skolkovo Inst Sci & Technol, Skolkovo, Russia..
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 1, p. 36-+Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 51, no 1, p. 36-+
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Biological Sciences
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URN: urn:nbn:se:kth:diva-240991DOI: 10.1038/s41588-018-0285-7ISI: 000454108800011PubMedID: 30510240Scopus ID: 2-s2.0-85058128183OAI: oai:DiVA.org:kth-240991DiVA, id: diva2:1277478
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QC 20190110

Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-15Bibliographically approved

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Akkuratov, Evgeny E.

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