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

Autori
Supek, Fran ; Lenher, Ben

Izvornik
Cell (0092-8674) 170 (2017), 3; 534-547

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

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

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Računarstvo

POVEZANOST RADA