Role of DNA Polymerases in Repeat-Mediated Genome Instability
Cell Rep. 2012 Nov 7. pii: S2211-1247(12)00342-7. doi: 10.1016/j.celrep.2012.10.006. [Epub ahead of print]
Role of DNA Polymerases in Repeat-Mediated Genome Instability.
Shah KA, Shishkin AA, Voineagu I, Pavlov YI, Shcherbakova PV, Mirkin SM.
Department of Biology, Tufts University, Medford, MA 02155, USA.
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.