FAAP20 (Fanconi Anemia Associated Protein 20) is a critical component of the Fanconi anemia (FA) core complex that plays essential roles in DNA damage response and repair. The protein functions as a ubiquitin reader, specifically recognizing K63-linked polyubiquitin chains through its conserved ubiquitin-binding zinc-finger (UBZ) domain to recruit the FA complex to DNA interstrand cross-links (ICLs) 1. Beyond canonical ubiquitin recognition, FAAP20's C-terminal tail forms an extended β-loop that enhances binding specificity and affinity, with the invariant C-terminal tryptophan being indispensable for function 1. FAAP20 promotes homology-directed repair of DNA double-strand breaks through both FANCA-dependent and FANCA-independent mechanisms, supporting homologous recombination and single-strand annealing pathways 2. The protein also facilitates translesion synthesis by interacting with REV1 through distinct binding surfaces on its UBZ4 domain 3. Loss of FAAP20 results in hematopoietic stem cell depletion under genotoxic stress and causes cellular hypersensitivity to DNA crosslinking agents 4. Clinically, FAAP20 mutations contribute to chemotherapy resistance in colorectal cancer by enhancing DNA repair pathway activation 5, while its loss in Antarctic icefish may contribute to their unique hematological adaptations 6.