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Role of DNA polymerases in repeat-mediated genome instability.

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 ? 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 ? and ? strongly increased rates for both repeat expansions and RIM. The increases in repeat-mediated instability observed in DNA polymerase ? mutants depended on translesion DNA polymerases. We conclude that repeat expansions and RIM are two sides of the same replicative mechanism.

SUBMITTER: Shah KA

PROVIDER: S-EPMC3513503 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Role of DNA polymerases in repeat-mediated genome instability.

Shah Kartik A KA Shishkin Alexander A AA Voineagu Irina I Pavlov Youri I YI Shcherbakova Polina V PV Mirkin Sergei M SM

Cell reports 20121108 5

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 ...[more]

PMID: 23142667

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