{"database":"ENA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"center_name":["Institute of Research in Biomedicine","IRB"],"full_dataset_link":["https://www.ebi.ac.uk/ena/browser/view/PRJEB91651"],"long_description":["Triplet repeat expansions underlie multiple pathologies, including Huntington’s disease, often aris-ing 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 MutL (MLH1-MLH3), stimulated by MutS (MSH2-MSH3), incises DNA opposite an extrahelical loop on the 5' side. This activity, with moderate sequence preference, generates DNA nicks enabling Pol-mediated displacement synthesis with the loop as a template, leading to expansions. PCNA con-fines these MutL 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, Pol re-moves the loop and resynthesizes DNA, causing contraction. FAN1 also directly inhibits MutL, preventing its activation by MutS. Our study illuminates both repeat expansion and contraction mechanisms and reveal the protective function of FAN1."],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"Mechanism of trinucleotide repeat expansion by MutSβ-MutL and contraction by FAN1","description":"Triplet repeat expansions underlie multiple pathologies, including Huntington’s disease, often aris-ing 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 MutL (MLH1-MLH3), stimulated by MutS (MSH2-MSH3), incises DNA opposite an extrahelical loop on the 5' side. This activity, with moderate sequence preference, generates DNA nicks enabling Pol-mediated displacement synthesis with the loop as a template, leading to expansions. PCNA con-fines these MutL 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, Pol re-moves the loop and resynthesizes DNA, causing contraction. FAN1 also directly inhibits MutL, preventing its activation by MutS. Our study illuminates both repeat expansion and contraction mechanisms and reveal the protective function of FAN1.","dates":{"last_updated":"2025-07-03","first_public":"2025-07-03"},"accession":"PRJEB91651","cross_references":{}}