Trinucleotide repeats can form secondary structures, whose inappropriate repair or replication can lead to repeat expansions. There are multiple loci within the human genome where expansion of trinucleotide repeats leads to disease. Although it is known that expanded repeats accumulate double-strand breaks (DSBs), it is not known which DSB repair pathways act on such lesions and whether inaccurate DSB repair pathways contribute to repeat expansions. Using Saccharomyces cerevisiae, we found that CAG/CTG tracts of 70 or 155 repeats exhibited significantly elevated levels of breakage and expansions in strains lacking MRE11, implicating the Mre11/Rad50/Xrs2 complex in repairing lesions at structure-forming repeats. About two-thirds of the expansions that occurred in the absence of MRE11 were dependent on RAD52, implicating aberrant homologous recombination as a mechanism for generating expansions. Expansions were also elevated in a sae2 deletion background and these were not dependent on RAD52, supporting an additional role for Mre11 in facilitating Sae2-dependent hairpin processing at the repeat. Mre11 nuclease activity and Tel1-dependent checkpoint functions were largely dispensable for repeat maintenance. In addition, we found that intact homologous recombination and nonhomologous end-joining pathways of DSB repair are needed to prevent repeat fragility and that both pathways also protect against repeat instability. We conclude that failure of principal DSB repair pathways to repair breaks that occur within the repeats can result in the accumulation of atypical intermediates, whose aberrant resolution will then lead to CAG expansions, contractions, and repeat-mediated chromosomal fragility.
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Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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Site | Modification | Modifier | Source | Reference |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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Evidence ID | Analyze ID | File | Description |
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