Title: Role of DNA polymerases in repeat-mediated genome instability.
Authors: Shah, Kartik A; Shishkin, Alexander A; Voineagu, Irina; Pavlov, Youri I; Shcherbakova, Polina V; Mirkin, Sergei M
Published In Cell Rep, (2012 Nov 29)
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.
PubMed ID: 23142667
MeSH Terms: DNA Polymerase I/genetics; DNA Polymerase I/metabolism*; DNA Polymerase II/genetics; DNA Polymerase II/metabolism*; DNA Polymerase III/genetics; DNA Polymerase III/metabolism*; DNA/genetics; Genomic Instability*; Introns; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism*; Saccharomyces cerevisiae/metabolism; Statistics, Nonparametric; Trinucleotide Repeat Expansion