Journal
SCIENCE ADVANCES
Volume 7, Issue 31, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf7906
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Funding
- Swiss National Science Foundation [31003A_176161, PP00P3_179057]
- Swiss Cancer Research Foundation [KFS-4702-02-2019]
- European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation program (ERC-2016-STG) [714326]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INBS-0005]
- Fondation ARC pour la Recherche sur la Cancer
- Petroff Family Fund
- Kazman Family Fund
- Marigold Foundation
- Canada Foundation for Innovation
- Canadian Institutes for Health Research (CIHR) [FRN148910]
- Natural Sciences and Engineering Research Council (NSERC)
- European Research Council (ERC) [714326] Funding Source: European Research Council (ERC)
- Swiss National Science Foundation (SNF) [31003A_176161, PP00P3_179057] Funding Source: Swiss National Science Foundation (SNF)
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The FAN1-MLH1 complex plays a crucial role in the response to ICL damage and repeat stability, with specific amino acid residues identified as critical for MLH1 binding. Disruption of the FAN1-MLH1 interaction may lead to cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs.
FAN1, a DNA structure-specific nuclease, interacts with MLH1, but the repair pathways in which this complex acts are unknown. FAN1 processes DNA interstrand crosslinks (ICLs) and FAN1 variants are modifiers of the neurodegenerative Huntington's disease (HD), presumably by regulating HD-causing CAG repeat expansions. Here, we identify specific amino acid residues in two adjacent FAN1 motifs that are critical for MLH1 binding. Disruption of the FAN1-MLH1 interaction confers cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs, intermediates of repeat expansion mutations. FAN1-S126 phosphorylation, which hinders FAN1-MLH1 association, is cell cycle-regulated by cyclin-dependent kinase activity and attenuated upon ICL induction. Our data highlight the FAN1-MLH1 complex as a phosphorylation-regulated determinant of ICL response and repeat stability, opening novel paths to modify cancer and neurodegeneration.
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