Structure-forming CAG/CTG repeat sequences are sensitive to breakage in the absence of Mrc1 checkpoint function and S-phase checkpoint signaling: implications for trinucleotide repeat expansion diseases.
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 approximately 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.
Freudenreich
Catherine H
CH
Department of Biology, Tufts University, Medford, Massachusetts 02155, USA. Catherine.Freudenreich@tufts.edu
Lahiri
Mayurika
M
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D042966:Cytochrome-B(5) Reductase / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D042822:Genomic Instability; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D009223:Myotonic Dystrophy / Q000235:genetics; D009690:Nucleic Acid Conformation; D016196:S Phase; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C488158:CLSPN protein, human; C022262:Okazaki fragments; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D042966:Cytochrome-B(5) Reductase; C470363:MCR1 protein, S cerevisiae