Slipped (CTG)*(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair
- PMID: 16025129
- DOI: 10.1038/nsmb959
Slipped (CTG)*(CAG) repeats can be correctly repaired, escape repair or undergo error-prone repair
Abstract
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 beta 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.
Comment in
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Toward a unified theory for repeat expansions.Nat Struct Mol Biol. 2005 Aug;12(8):635-7. doi: 10.1038/nsmb0805-635. Nat Struct Mol Biol. 2005. PMID: 16077722 No abstract available.
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