Journal article
DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine
- Abstract:
- Transitions of cytosine to thymine in CpG dinucleotides are the most frequent type of mutations observed in cancer. This increased mutability is commonly explained by the presence of 5-methylcytosine (5mC) and its spontaneous hydrolytic deamination into thymine. Here, we describe observations that question whether spontaneous deamination alone causes the elevated mutagenicity of 5mC. Tumours with somatic mutations in DNA mismatch-repair genes or in the proofreading domain of DNA polymerase ε (Pol ε) exhibit more 5mC to T transitions than would be expected, given the kinetics of hydrolytic deamination. This enrichment is asymmetrical around replication origins with a preference for the leading strand template, in particular in methylated cytosines flanked by guanines (GCG). Notably, GCG to GTG mutations also exhibit strand asymmetry in mismatch-repair and Pol ε wild-type tumours. Together, these findings suggest that mis-incorporation of A opposite 5mC during replication of the leading strand might be a contributing factor in the mutagenesis of methylated cytosine.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Accepted manuscript, pdf, 1.5MB, Terms of use)
-
(Preview, Accepted manuscript, pdf, 1.5MB, Terms of use)
-
(Preview, Accepted manuscript, pdf, 112.8KB, Terms of use)
-
- Publisher copy:
- 10.1016/j.dnarep.2017.11.005
Authors
- Publisher:
- Elsevier
- Journal:
- DNA Repair More from this journal
- Volume:
- 62
- Pages:
- 1-7
- Publication date:
- 2017-11-24
- Acceptance date:
- 2017-11-21
- DOI:
- ISSN:
-
1568-7856
- Keywords:
- Pubs id:
-
pubs:798389
- UUID:
-
uuid:ab6b6334-d70b-4b98-a9d7-95da761e011c
- Local pid:
-
pubs:798389
- Source identifiers:
-
798389
- Deposit date:
-
2017-11-28
Terms of use
- Copyright holder:
- Elsevier BV
- Copyright date:
- 2017
- Notes:
-
Copyright © 2017 Elsevier B.V. This is the accepted manuscript version of the article. The final version is available online from Elsevier at: https://doi.org/10.1016/j.dnarep.2017.11.005
Note: an erratum exists for this article, originally published and available at: https://doi.org/10.1016/j.dnarep.2018.02.008
If you are the owner of this record, you can report an update to it here: Report update to this record