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PMID: 21406975 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

Damage-induced localized hypermutability.

Cell cycle (Georgetown, Tex.) ·Vol. 10 ·No. 7 ·2011-04-01 ·Pages 1073-85

Burch LH, Yang Y, Sterling JF, Roberts SA, Chao FG, Xu H, Zhang L, Walsh J, Resnick MA, Mieczkowski PA, Gordenin DA

Abstract

Genome instability continuously presents perils of cancer, genetic disease and death of a cell or an organism. At the same time, it provides for genome plasticity that is essential for development and evolution. We address here the genome instability confined to a small fraction of DNA adjacent to free DNA ends at uncapped telomeres and double-strand breaks. We found that budding yeast cells can tolerate nearly 20 kilobase regions of subtelomeric single-strand DNA that contain multiple UV-damaged nucleotides. During restoration to the double-strand state, multiple mutations are generated by error-prone translesion synthesis. Genome-wide sequencing demonstrated that multiple regions of damage-induced localized hypermutability can be tolerated, which leads to the simultaneous appearance of multiple mutation clusters in the genomes of UV- irradiated cells. High multiplicity and density of mutations suggest that this novel form of genome instability may play significant roles in generating new alleles for evolutionary selection as well as in the incidence of cancer and genetic disease.

MeSH Terms
DNA Breaks, Double-Stranded/radiation effects DNA Damage/genetics,radiation effects Genetic Variation Genomic Instability/genetics Mutation/radiation effects Saccharomyces cerevisiae Proteins/genetics Saccharomycetales Sequence Analysis, DNA Telomere/genetics,radiation effects Telomere-Binding Proteins/genetics Ultraviolet Rays
Chemicals
Cdc13 protein, S cerevisiae Saccharomyces cerevisiae Proteins Telomere-Binding Proteins
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Burch Lauranell H
National Institute of Environmental Health Sciences, Research Triangle Park, NC USA.
Yang Yong
Sterling Joan F
Roberts Steven A
Chao Frank G
Xu Hong
Zhang Leilei
Walsh Jesse
Resnick Michael A
Mieczkowski Piotr A
Gordenin Dmitry A
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Article Info
Journal
Cell cycle (Georgetown, Tex.)
Abbr.
Cell Cycle
ISSN
1551-4005
DOI
10.4161/cc.10.7.15319
Published
2011-04-01
Epub
2011-00-01
Pages
1073-85
Language
English
Region
United States
NLM ID
101137841
PMCID
PMC3100884
Subset
IM
Grants
NIEHS NIH HHS · P30 ES010126 · United States
NIEHS NIH HHS · RC1 ES018091 · United States
Intramural NIH HHS · Z01 ES065073 · United States
NIEHS NIH HHS · P30ES010126 · United States
External Links
PubMed source DOI: 10.4161/cc.10.7.15319 PMC Full Text View journal details
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