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Loss of MLH1 function causes MMR deficiency (MMRd), leading to elevated mutation rates and increased cancer susceptibility. However, MMRd can offer a therapeutic advantage, as high tumour mutational burden enhances the efficacy of immune checkpoint inhibition. MMR also drives somatic expansion of CAG repeats linked to Huntington\u2019s disease (HD) pathogenesis. The C-terminal domain (CTD) of MLH1 contains at least two distinct protein\u2013protein interaction (PPI) sites. The S1 site supports heterodimerization with the PMS2 endonuclease, whereas the S2 site interacts with MIP-boxes present in MMR-associated factors (EXO1, MSH3) and in the DNA repair nuclease FAN1. Here, using MLH1-S2 mutant cell models and synthetic FAN1-derived peptides containing two adjacent MLH1-binding motifs (MIP and MIM), we demonstrate that selective disruption of MLH1 PPIs impairs MMR in vitro. We further reveal that the peptide is able to inhibit the latent endonuclease activity of recombinant MutL\u03b1, possibly via competing with a putative MIM within PMS2. Our findings define key PPI interfaces within the MLH1(CTD) that govern MMR activity and may offer novel therapeutic opportunities to exploit MMRd in cancer and HD.<\/jats:p>","DOI":"10.1093\/narcan\/zcaf055","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T13:01:35Z","timestamp":1764248495000},"source":"Crossref","is-referenced-by-count":4,"title":["Disruption of protein\u2013protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency"],"prefix":"10.1093","volume":"7","author":[{"given":"Keri M","family":"Fishwick","sequence":"first","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Gomez\u00a0Vieito","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Greco","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Collotta","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Gatti","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasija\u00a0A","family":"Kulik","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-2858","authenticated-orcid":false,"given":"Rapha\u00ebl","family":"Gu\u00e9rois","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC) , 91198 Gif-sur-Yvette ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Corbeski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashutosh S","family":"Phadte","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, PA 19107 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issam","family":"Senoussi","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 della Svizzera Italiana (USI) , CH-6500 Bellinzona ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9087-032X","authenticated-orcid":false,"given":"Petr","family":"Cejka","sequence":"additional","affiliation":[{"name":"Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Universit\u00e0 della Svizzera Italiana (USI) , CH-6500 Bellinzona ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4868-6024","authenticated-orcid":false,"given":"Anna","family":"Pluciennik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University , Philadelphia, PA 19107 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Porro","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2770-0333","authenticated-orcid":false,"given":"Alessandro A","family":"Sartori","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , Strickhofstrasse 40a, CH-8057 Zurich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"2025123107421268600_B1","doi-asserted-by":"publisher","first-page":"a012633","DOI":"10.1101\/cshperspect.a012633","article-title":"Postreplicative mismatch repair","volume":"5","author":"Jiricny","year":"2013","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025123107421268600_B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/cr.2007.115","article-title":"Mechanisms and functions of DNA mismatch repair","volume":"18","author":"Li","year":"2008","journal-title":"Cell Res"},{"key":"2025123107421268600_B3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.dnarep.2015.04.010","article-title":"Exonuclease 1-dependent and independent mismatch repair","volume":"32","author":"Goellner","year":"2015","journal-title":"DNA 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