ArticleNature communications2025
Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
3 citing papers in PubMed.
- Replication associated nuclear DNA mismatch repair across kingdoms.Biochemical Society transactions · 2026Review
- Mismatch repair MLH complexes make distinct contributions to post-replicative mismatch repair versus trinucleotide repeat expansions.bioRxiv : the preprint server for biology · 2026Article
- Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency.NAR cancer · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
Triplet repeat expansion underlies multiple pathologies, including Huntington's disease, often arising in somatic non-dividing tissues such as the brain. Despite identification of genetic modifiers, mechanistic insights remain limited. Using purified human proteins, we show that MutLγ (MLH1-MLH3), stimulated by MutSβ (MSH2-MSH3), incises DNA opposite an extrahelical loop on the 5' side. This activity, with a moderate sequence preference, generates DNA nicks enabling Polδ-mediated displacement synthesis with the loop as a template, leading to expansion. PCNA confines these MutLγ incisions near the loop. FAN1, instead, preferentially targets the looped strand. RFC-PCNA stimulate and direct FAN1 nuclease to the 3' boundary of the loop while restricting its exonuclease activity. No pre-existing nick is required. Following FAN1-RFC-PCNA action, Polδ removes the loop and resynthesizes DNA, causing contraction. FAN1 also directly inhibits MutLγ, preventing its activation by MutSβ. Our study illuminates both repeat expansion and contraction mechanisms and reveals the protective function of FAN1.
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