ArticleProceedings of the National Academy of Sciences of the United States of America2010
Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSbeta, but clustered slip-outs are poorly repaired.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 97 citations in OpenAlex.
- Somatic CRISPR editing ofbioRxiv : the preprint server for biology · 2026Article
- Expanding repeats, expanding impact: Somatic instability in myotonic dystrophy type 1.Journal of neuromuscular diseases · 2026Review
- Huntington's disease LIG1 modifier variant increases ligase fidelity and suppresses somatic CAG repeat expansion.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism.American journal of human genetics · 2026Article
- Inherent instability of simple DNA repeats shapes an evolutionarily stable distribution of repeat lengths.Nature communications · 2025Article
- In vivo CRISPR-Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington's disease.Nature genetics · 2025Article
- Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum.Nature genetics · 2024Article
- Article
- Structures and conformational dynamics of DNA minidumbbells in pyrimidine-rich repeats associated with neurodegenerative diseases.Computational and structural biotechnology journal · 2023Review
- Exome sequencing of individuals with Huntington's disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset.Nature neuroscience · 2022Article
- Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing.Human molecular genetics · 2022Article
- FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats.Science advances · 2021Article
- Review
- FAN1, a DNA Repair Nuclease, as a Modifier of Repeat Expansion Disorders.Journal of Huntington's disease · 2021Review
- Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models.Journal of Huntington's disease · 2021Review
- DNA Mismatch Repair and its Role in Huntington's Disease.Journal of Huntington's disease · 2021Review
- On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability.The Journal of biological chemistry · 2020Review
- A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.Nature genetics · 2020Article
- The G-rich Repeats inGenetics · 2018Article
- The central role of DNA damage and repair in CAG repeat diseases.Disease models & mechanisms · 2018Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
Expansions of CTG/CAG trinucleotide repeats, thought to involve slipped DNAs at the repeats, cause numerous diseases including myotonic dystrophy and Huntington's disease. By unknown mechanisms, further repeat expansions in transgenic mice carrying expanded CTG/CAG tracts require the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSbeta complex. Using an in vitro repair assay, we investigated the effect of slip-out size, with lengths of 1, 3, or 20 excess CTG repeats, as well as the effect of the number of slip-outs per molecule, on the requirement for human MMR. Long slip-outs escaped repair, whereas short slip-outs were repaired efficiently, much greater than a G-T mismatch, but required hMutSbeta. Higher or lower levels of hMutSbeta or its complete absence were detrimental to proper repair of short slip-outs. Surprisingly, clusters of as many as 62 short slip-outs (one to three repeat units each) along a single DNA molecule with (CTG)50*(CAG)50 repeats were refractory to repair, and repair efficiency was reduced further without MMR. Consistent with the MutSbeta requirement for instability, hMutSbeta is required to process isolated short slip-outs; however, multiple adjacent short slip-outs block each other's repair, possibly acting as roadblocks to progression of repair and allowing error-prone repair. Results suggest that expansions can arise by escaped repair of long slip-outs, tandem short slip-outs, or isolated short slip-outs; the latter two types are sensitive to hMutSbeta. Poor repair of clustered DNA lesions has previously been associated only with ionizing radiation damage. Our results extend this interference in repair to neurodegenerative disease-causing mutations in which clustered slip-outs escape proper repair and lead to expansions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.