Role of DNA polymerases in repeat-mediated genome instability.
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.
Mesh Terms:
DNA, DNA Polymerase I, DNA Polymerase II, DNA Polymerase III, Genomic Instability, Introns, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Statistics, Nonparametric, Trinucleotide Repeat Expansion
DNA, DNA Polymerase I, DNA Polymerase II, DNA Polymerase III, Genomic Instability, Introns, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Statistics, Nonparametric, Trinucleotide Repeat Expansion
Cell Rep
Date: Nov. 29, 2012
PubMed ID: 23142667
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