Clustered Mutations in Yeast and in Human Cancers Can Arise from Damaged Long Single-strand DNA Regions

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 May 22

PMID 22607975

Citations 268

Authors

Steven A Roberts

Joan Sterling

Cole Thompson

Shawn Harris

Deepak Mav

Ruchir Shah

Leszek J Klimczak

Gregory V Kryukov

Ewa Malc

Piotr A Mieczkowski

Michael A Resnick

Dmitry A Gordenin

Affiliations

Soon will be listed here.

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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