FAN1 is a 5'-3' exonuclease and endonuclease that functions as a critical nuclease in DNA interstrand crosslink (ICL) repair 1. The protein is recruited to DNA damage sites by monoubiquitinated FANCD2 and operates through a strand-directed nuclease mechanism that cleaves DNA at intervals to excise ICLs from one strand via flanking incisions 2. FAN1 also removes triplet repeat extrusions through a PCNA- and RFC-dependent mechanism, with PCNA conferring strand directionality to the nuclease and requiring physical interaction between these proteins 3. This function is particularly relevant to Huntington's disease, where FAN1 prevents somatic CAG repeat expansion through very short patch excision-repair that competes with mismatch repair proteins 3. Genome-wide association studies identified FAN1 as a genetic modifier of Huntington's disease age of onset, with effects differentially influencing motor and cognitive domains 4. Cell-type-specific analysis reveals that elevated MSH2/MSH3 levels in striatal neurons inhibit FAN1-mediated nucleolytic excision of CAG slip-outs, suggesting a key antagonistic relationship in repeat expansion control 5. FAN1 mutations associate with various cancers and degenerative diseases, underscoring its importance in maintaining chr15 stability 1.