Nature Structural & Molecular Biology
12, 654 - 662 (2005)
Published online: 17 July 2005; | doi:10.1038/nsmb959
Slipped (CTG) (CAG) repeats can be correctly repaired, escape repair or undergo error-prone repairGagan B Panigrahi, Rachel Lau, S Erin Montgomery, Michelle R Leonard
& Christopher E Pearson
Program of Genetics & Genomic Biology, The Hospital for Sick Children, 555 University Avenue, Elm Wing 11-135, Toronto, Ontario M5G 1X8, Canada, and Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Correspondence should be addressed to Christopher E Pearson cepearson@genet.sickkids.on.ca Expansion of (CTG)(CAG) repeats, the cause of 14 or more diseases, is presumed to arise through escaped repair of slipped DNAs. We report the fidelity of slipped-DNA repair using human cell extracts and DNAs with slip-outs of (CAG)20 or (CTG)20. Three outcomes occurred: correct repair, escaped repair and error-prone repair. The choice of repair path depended on nick location and slip-out composition (CAG or CTG). A new form of error-prone repair was detected whereby excess repeats were incompletely excised, constituting a previously unknown path to generate expansions but not deletions. Neuron-like cell extracts yielded each of the three repair outcomes, supporting a role for these processes in (CTG)(CAG) instability in patient post-mitotic brain cells. Mismatch repair (MMR) and nucleotide excision repair (NER) proteins hMSH2, hMSH3, hMLH1, XPF, XPG or polymerase  were not required—indicating that their role in instability may precede that of slip-out processing. Differential processing of slipped repeats may explain the differences in mutation patterns between various disease loci or tissues.
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