Ubiquitin-specific-processing protease 1 (USP1) (USP1)

Ubiquitin-specific-processing protease 1 (USP1) is a critical deubiquitinating enzyme (DUB) that functions as a master regulator of the DNA damage response (DDR) [1.1.1, 1.3.1]. It operates primarily in a stable heterodimeric complex with its essential cofactor, USP1-associated factor 1 (UAF1), which allosterically enhances its catalytic activity and facilitates substrate recognition [1.1.1, 1.3.1]. The USP1/UAF1 complex is responsible for deubiquitinating key proteins such as monoubiquitinated PCNA and the FANCI-FANCD2 complex, thereby controlling the termination of translesion synthesis and the Fanconi anemia repair pathway [1.1.2, 1.1.4]. In many cancers, including ovarian, breast, and lung carcinomas, USP1 is overexpressed and contributes to tumor survival by maintaining genomic stability and promoting resistance to DNA-damaging therapies like cisplatin and PARP inhibitors [1.3.1, 1.3.4]. This makes USP1 a high-priority therapeutic target, particularly for inducing synthetic lethality in tumors with homologous recombination deficiency (HRD), such as those harboring BRCA1 or BRCA2 mutations [1.1.2, 1.4.4]. Several small-molecule inhibitors, including KSQ-4279 (RO7623066) and ISM3091 (XL309), are currently undergoing clinical evaluation as monotherapies or in combination with other DDR-targeted agents [1.4.1, 1.4.5]. However, clinical development faces challenges such as managing hematological toxicities like anemia and potential liver toxicity, as seen with some early-stage candidates like TNG348 [1.4.2, 1.4.3].

Other names

USP1USP1/UAF1 complexUbiquitin specific peptidase 1Ubiquitin carboxyl-terminal hydrolase 1WDR48-USP1 complexp80-USP1 complex

Allosteric inhibition of the deubiquitinating activity of the USP1/UAF1 complex, leading to the accumulation of monoubiquitinated PCNA and FANCD2, which induces replication stress and synthetic lethality in HRD-deficient cells [1.1.2, 1.4.4].