Shah KA, et al. (2012) Role of DNA polymerases in repeat-mediated genome instability. Cell Rep 2(5):1088-95
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 a 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 d and e strongly increased rates for both repeat expansions and RIM. The increases in repeat-mediated instability observed in DNA polymerase d mutants depended on translesion DNA polymerases. We conclude that repeat expansions and RIM are two sides of the same replicative mechanism.
|Status: Published||Type: Journal Article||PubMed ID: 23142667|
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