Error-free and error-prone DNA repair shape mutation landscapes in human tumors
Tipus de documentText en actes de congrés
Data publicació2020
EditorBarcelona Supercomputing Center
Condicions d'accésAccés obert
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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.
CitacióSupek, F. Error-free and error-prone DNA repair shape mutation landscapes in human tumors. A: . Barcelona Supercomputing Center, 2020, p. 9-10.
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