ALBERT

Beschreibung: 29 November 2012 Publication year: 2012 Source: Cell Reports, Volume 2, Issue 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 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. Graphical abstract Highlights ► Elementary step of repeat expansion corresponds to size of an Okazaki fragment ► Mutated DNA polymerase α leads to an increase in expansion step ► Mutated DNA polymerases δ and ε lead to elevated expansion rates ► Repeats induce mutagenesis, which is further elevated in polymerase mutants