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

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.
PMID
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Authors

Mayor MeshTerms

DNA Mismatch Repair

Mutation

Keywords

cancer genomics

epigenetic marks

euchromatin

localized hypermutation

mismatch repair

oncogenes

somatic single-nucleotide variants

translesion DNA synthesis

Journal Title cell
Publication Year Start




PMID- 28753428
OWN - NLM
STAT- MEDLINE
DA  - 20170728
DCOM- 20170808
LR  - 20170808
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 170
IP  - 3
DP  - 2017 Jul 27
TI  - Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets
      Mutations to Active Genes.
PG  - 534-547.e23
LID - S0092-8674(17)30774-2 [pii]
LID - 10.1016/j.cell.2017.07.003 [doi]
AB  - 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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Supek, Fran
AU  - Supek F
AD  - 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.
FAU - Lehner, Ben
AU  - Lehner B
AD  - 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; Institucio Catalana de Recerca i Estudis
      Avancats (ICREA), 08010 Barcelona, Spain. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - EC 2.7.7.7 (DNA-Directed DNA Polymerase)
RN  - EC 2.7.7.7 (Rad30 protein)
RN  - EC 3.5.4.1 (APOBEC3 protein, human)
RN  - EC 3.5.4.1 (Cytosine Deaminase)
SB  - IM
MH  - Cytosine Deaminase/genetics
MH  - *DNA Mismatch Repair
MH  - DNA-Directed DNA Polymerase/genetics
MH  - Humans
MH  - Liver Neoplasms/chemically induced/genetics
MH  - Melanoma/genetics
MH  - Mutagenesis
MH  - *Mutation
MH  - Neoplasms/*genetics
MH  - Smoking/adverse effects
MH  - Ultraviolet Rays/adverse effects
OTO - NOTNLM
OT  - cancer genomics
OT  - epigenetic marks
OT  - euchromatin
OT  - localized hypermutation
OT  - mismatch repair
OT  - oncogenes
OT  - somatic single-nucleotide variants
OT  - translesion DNA synthesis
EDAT- 2017/07/29 06:00
MHDA- 2017/08/09 06:00
CRDT- 2017/07/29 06:00
PHST- 2017/01/26 [received]
PHST- 2017/05/17 [revised]
PHST- 2017/07/05 [accepted]
AID - S0092-8674(17)30774-2 [pii]
AID - 10.1016/j.cell.2017.07.003 [doi]
PST - ppublish
SO  - Cell. 2017 Jul 27;170(3):534-547.e23. doi: 10.1016/j.cell.2017.07.003.