Open AccessRole of DNA Polymerases in Repeat-Mediated Genome Instability
Author(s) -
Kartik Shah,
A.A. Shishkin,
Irina Voineagu,
Youri I. Pavlov,
Polina V. Shcherbakova,
Sergei M. Mirkin
Publication year - 2012
Publication title -
cell reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.264
H-Index - 154
eISSN - 2639-1856
pISSN - 2211-1247
DOI - 10.1016/j.celrep.2012.10.006
Subject(s) - okazaki fragments , dna polymerase , biology , polymerase , dna polymerase ii , genetics , dna replication , primase , dna clamp , dna , dna polymerase i , microbiology and biotechnology , primer (cosmetics) , polymerase chain reaction , eukaryotic dna replication , chemistry , gene , reverse transcriptase , organic chemistry
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.
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