title: 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 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.
authors.affiliation: Department of Biology, Tufts University, Medford, MA 02155, USA.
authors.forename: Kartik A
authors.initials: KA
authors.lastname: Shah
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shishkin
authors.forename: Irina
authors.initials: I
authors.lastname: Voineagu
authors.forename: Youri I
authors.initials: YI
authors.lastname: Pavlov
authors.forename: Polina V
authors.initials: PV
authors.lastname: Shcherbakova
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Mirkin
mesh_terms: D004247:DNA / Q000235:genetics; D004256:DNA Polymerase I / Q000235:genetics / Q000378:metabolism*; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism*; D042822:Genomic Instability; D007438:Introns; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D019680:Trinucleotide Repeat Expansion
chemical_list: C022262:Okazaki fragments; D029701:Saccharomyces cerevisiae Proteins; C554167:URA3 protein, S cerevisiae; D004247:DNA; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D004258:DNA Polymerase III