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Cell. 2017 Jul 27;170(3):534-547.e23. doi: 10.1016/j.cell.2017.07.003.

Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets Mutations to Active Genes.

Author information

1
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Division of Electronics, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
2
EMBL-CRG Systems Biology Unit, Centre for Genomic Regulation (CRG), the Barcelona Institute of Science and Technology, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain. Electronic address: ben.lehner@crg.eu.

Abstract

Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.

KEYWORDS:

cancer genomics; epigenetic marks; euchromatin; localized hypermutation; mismatch repair; oncogenes; somatic single-nucleotide variants; translesion DNA synthesis

PMID:
28753428
DOI:
10.1016/j.cell.2017.07.003
[Indexed for MEDLINE]
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