Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions

Mol Cell. 2012 May 25;46(4):424-35. doi: 10.1016/j.molcel.2012.03.030. Epub 2012 May 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Basic / genetics
  • DNA Breaks, Double-Stranded*
  • DNA Methylation / genetics
  • DNA Repair
  • DNA, Fungal / genetics*
  • DNA, Neoplasm / genetics*
  • DNA, Single-Stranded / genetics*
  • Genes, Fungal
  • Genes, Reporter
  • Humans
  • Methyl Methanesulfonate
  • Mutagens
  • Mutation*
  • Neoplasms / genetics*
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics


  • Amino Acid Transport Systems, Basic
  • CAN1 protein, S cerevisiae
  • DNA, Fungal
  • DNA, Neoplasm
  • DNA, Single-Stranded
  • Mutagens
  • Saccharomyces cerevisiae Proteins
  • URA3 protein, S cerevisiae
  • Methyl Methanesulfonate