Journal
CELL CYCLE
Volume 3, Issue 11, Pages 1370-1374Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.3.11.1246
Keywords
trinucleotide repeat; inherited genetic disease; DNA damage; checkpoint proteins; Mrc1; Claspin; stability; fragility; DNA repair
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Funding
- NIGMS NIH HHS [R01 GM063066] Funding Source: Medline
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Expansion of trinucleotide repeat sequences is the cause of multiple inherited human genetic diseases including Huntington's disease and myotonic dystrophy. CTG and CAG repeats have been shown to form stable secondary structures that can impair Okazaki fragment processing and may impede replication fork progression. We recently showed that mutation of DNA damage checkpoint proteins results in increased chromosome breaks at expanded CAG/CTG repeats and in increased repeat instability ( expansions and contractions). 1 Here we report that long CAG similar to 155 tracts are especially sensitive to the absence of Mrc1 ( Claspin) checkpoint function, implicating the S-phase checkpoint in maintenance of trinucleotide repeats and other secondary-structure forming sequences. Based on all of our results, we propose a model for the detection of different types of structures by different checkpoint signaling pathways.
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