Ubiquitin carboxyl-terminal hydrolase 1 (USP1) (USP1)

Ubiquitin carboxyl-terminal hydrolase 1 (USP1) is a deubiquitinating enzyme that plays a pivotal role in the DNA damage response (DDR) by regulating the ubiquitination status of key proteins involved in DNA repair. USP1 functions as a heterodimeric complex with its essential cofactor, USP1-associated factor 1 (UAF1, also known as WDR48), which significantly enhances its catalytic activity and substrate specificity. The complex is responsible for deubiquitinating monoubiquitinated PCNA and FANCD2, thereby controlling translesion synthesis and the Fanconi anemia pathway to maintain genomic stability. In cancers characterized by homologous recombination deficiency (HRD), such as those with BRCA1 or BRCA2 mutations, cells exhibit a synthetic lethal dependency on USP1 for survival. Therapeutic targeting of the USP1-UAF1 complex with small-molecule inhibitors aims to exploit this vulnerability, often in combination with PARP inhibitors or platinum-based chemotherapy. Several USP1 inhibitors, including KSQ-4279 and ISM3091, are currently undergoing clinical evaluation for the treatment of advanced solid tumors.

Other names

Ubiquitin specific peptidase 1Ubiquitin thioesterase 1Deubiquitinating enzyme 1hUBPUSP1-UAF1 complexWDR48-USP1 complex

Allosteric inhibition of the USP1-UAF1 complex, which prevents the deubiquitination of PCNA and FANCD2, leading to the accumulation of monoubiquitinated substrates, replication stress, and synthetic lethality in homologous recombination-deficient cells.