Role of DNA Polymerases in Repeat-Mediated Genome Instability

Kartik A. Shah, Alexander A. Shishkin, Irina Voineagu, Youri I. Pavlov, Polina V. Shcherbakova, Sergei M. Mirkin

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Expansions of simple DNA repeats cause numerous hereditary diseases in humans. We analyzed the role of DNA polymerases in the instability of Friedreich@s ataxia (GAA)n repeats in a yeast experimental system. The elementary step of expansion corresponded to ∼160 bp in the wild-type strain, matching the size of Okazaki fragments in yeast. This step increased when DNA polymerase α was mutated, suggesting a link between the scale of expansions and Okazaki fragment size. Expandable repeats strongly elevated the rate of mutations at substantial distances around them, a phenomenon we call repeat-induced mutagenesis (RIM). Notably, defects in the replicative DNA polymerases δ and ε strongly increased rates for both repeat expansions and RIM. The increases in repeat-mediated instability observed in DNA polymerase δ mutants depended on translesion DNA polymerases. We conclude that repeat expansions and RIM are two sides of the same replicative mechanism.

Original languageEnglish (US)
Pages (from-to)1088-1095
Number of pages8
JournalCell Reports
Volume2
Issue number5
DOIs
StatePublished - Nov 29 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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