Journal article
Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions
Molecular cell, Vol.46(4), pp.424-435
05/25/2012
Handle:
https://hdl.handle.net/2376/100789
PMCID: PMC3361558
PMID: 22607975
Abstract
Mutations are typically perceived as random, independent events. We describe here nonrandom clustered mutations in yeast and in human cancers. Genome sequencing of yeast grown under chronic alkylation damage identified mutation clusters that extend up to 200 kb. A predominance of “strand-coordinated” changes of either cytosines or guanines in the same strand, mutation patterns, and genetic controls indicated that simultaneous mutations were generated by base alkylation in abnormally long single-strand DNA (ssDNA) formed at double-strand breaks (DSBs) and replication forks. Significantly, we found mutation clusters with analogous features in sequenced human cancers. Strand-coordinated clusters of mutated cytosines or guanines often resided near chromosome rearrangement breakpoints and were highly enriched with a motif targeted by APOBEC family cytosine-deaminases, which strongly prefer ssDNA. These data indicate that hypermutation via multiple simultaneous changes in randomly formed ssDNA is a general phenomenon that may be an important mechanism producing rapid genetic variation.
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► Clusters of simultaneous multiple mutations occur in yeast and human genomes ► Mutation clusters can occur in damaged ssDNA during DSB repair or replication ► Clusters of coordinated C or G mutations in cancers colocalize with rearrangements ► Clustered mutations in cancers occur at motifs of cytosine deamination by APOBECs
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Details
- Title
- Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-Strand DNA Regions
- Creators
- Steven A Roberts - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USAJoan Sterling - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USACole Thompson - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USAShawn Harris - SRA International, Inc., Durham, NC 27709, USADeepak Mav - SRA International, Inc., Durham, NC 27709, USARuchir Shah - SRA International, Inc., Durham, NC 27709, USALeszek J Klimczak - Integrative Bioinformatics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USAGregory V Kryukov - The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USAEwa Malc - Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USAPiotr A Mieczkowski - Department of Genetics, Lineberger Comprehensive Cancer Center and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC 27599, USAMichael A Resnick - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USADmitry A Gordenin - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA
- Publication Details
- Molecular cell, Vol.46(4), pp.424-435
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Elsevier Inc
- Identifiers
- 99900546573601842
- Language
- English
- Resource Type
- Journal article