Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1.

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-existin

SUBMITTER: Senoussi I 

PROVIDER: S-EPMC12559329 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature