USP1 (ubiquitin specific peptidase 1) is a deubiquitinating enzyme that plays critical roles in DNA damage response and cellular homeostasis. USP1 functions as a negative regulator of DNA damage repair by specifically deubiquitinating monoubiquitinated FANCD2 and PCNA, thereby controlling translesion synthesis and interstrand crosslink repair pathways 1. The enzyme requires interaction with WDR48 for optimal catalytic activity and works to restrain PCNA degradation during DNA repair processes 2. Beyond DNA repair, USP1 regulates immune cell differentiation by deubiquitinating and stabilizing TAZ, promoting Th17 cell development while inhibiting regulatory T cell differentiation 3. In cancer biology, USP1 contributes to therapeutic resistance through multiple mechanisms, including stabilization of MAST1 protein to confer cisplatin resistance 4 and regulation of PARP1 trapping and PARylation activity 5. USP1 is particularly important in BRCA-mutant tumors, where it represents a synthetic lethal target, and USP1 inhibitors like KSQ-4279 show promise in overcoming PARP inhibitor resistance 6. The clinical significance of USP1 extends to ovarian cancer drug resistance and metabolic disorders, making it an attractive therapeutic target 78.