FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats.
Antonio PorroMohiuddin MohiuddinChristina ZurfluhVincent SpeggJingqi DaiFlorence IehlVirginie RoparsGiulio CollottaKeri M FishwickNour L MozaffariRaphaël GuéroisJosef JiricnyMatthias AltmeyerJean Baptiste CharbonnierChristopher E PearsonAlessandro A SartoriPublished in: Science advances (2021)
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.
Keyphrases
- cell cycle
- amino acid
- squamous cell carcinoma
- cell proliferation
- gene expression
- oxidative stress
- circulating tumor
- protein kinase
- healthcare
- machine learning
- cell free
- single molecule
- copy number
- electronic health record
- binding protein
- young adults
- artificial intelligence
- genome wide
- deep learning
- signaling pathway
- lymph node metastasis
- health insurance