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PMID: 24615916 Published · ppublish English Journal Article

Clustered and genome-wide transient mutagenesis in human cancers: Hypermutation without permanent mutators or loss of fitness.

BioEssays : news and reviews in molecular, cellular and developmental biology ·Vol. 36 ·No. 4 ·2014-00-00 ·Pages 382-393

Roberts SA, Gordenin DA

Abstract

The gain of a selective advantage in cancer as well as the establishment of complex traits during evolution require multiple genetic alterations, but how these mutations accumulate over time is currently unclear. There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers. While in some cases the increased mutation rate is the result of a genetic disruption of DNA repair and replication or environmental exposures, other evidence suggests that endogenous DNA damage induced by AID/APOBEC cytidine deaminases can result in transient localized hypermutation generating simultaneous, closely spaced (i.e. "clustered") multiple mutations. Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome-wide. This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators.

Keywords
APOBEC DNA damage DNA repair hypermutation kataegis mutation cluster
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Roberts Steven A
Chromosome Stability Group, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, NC, USA.
Gordenin Dmitry A
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Article Info
Journal
BioEssays : news and reviews in molecular, cellular and developmental biology
Abbr.
Bioessays
ISSN
1521-1878
DOI
10.1002/bies.201300140
Published
2014-00-00
Epub
2014-00-26
Pages
382-393
Language
English
Region
United States
NLM ID
8510851
PMCID
PMC4145046
Grants
NIEHS NIH HHS · R00 ES022633 · United States
Intramural NIH HHS · Z01 ES065073 · United States
Intramural NIH HHS · Z99 ES999999 · United States
External Links
PubMed source DOI: 10.1002/bies.201300140 PMC Full Text View journal details
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