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 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.
Original language | English (US) |
---|---|
Pages (from-to) | 1088-1095 |
Number of pages | 8 |
Journal | Cell Reports |
Volume | 2 |
Issue number | 5 |
DOIs | |
State | Published - Nov 29 2012 |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology