Ubiquitin-specific-processing protease 1 (USP1)

Ubiquitin-specific-processing protease 1 (USP1) is a critical deubiquitinating enzyme (DUB) belonging to the USP family, primarily recognized for its essential role in DNA damage response and repair pathways [1, 2]. It functions by removing monoubiquitin moieties from key substrates, most notably Proliferating Cell Nuclear Antigen (PCNA) and the FANCD2-FANCI complex, thereby regulating translesion synthesis and the Fanconi anemia DNA repair pathway [2, 3]. By modulating these processes, USP1 ensures genomic stability and prevents the accumulation of DNA lesions during replication [3]. In oncology, USP1 is frequently overexpressed in various cancers, such as ovarian, breast, and lung cancer, where it promotes tumor cell survival and contributes to resistance against DNA-damaging chemotherapies [4, 5]. Consequently, USP1 has emerged as a high-priority therapeutic target, particularly for inducing synthetic lethality in homologous recombination-deficient (HRD) tumors or in combination with PARP inhibitors [5, 6]. Several small-molecule inhibitors of USP1 are currently undergoing clinical evaluation to assess their safety and efficacy in treating advanced solid tumors [6, 7]. Sources: [1] UniProt P40818; [2] Huang et al. (2006) Nature Cell Biology; [3] Huang et al. (2006) Molecular Cell; [4] Ma et al. (2019) Frontiers in Oncology; [5] Mistry et al. (2020) Scientific Reports; [6] ClinicalTrials.gov (NCT05240898, NCT05932212); [7] Insilico Medicine/KSQ Therapeutics Pipeline.

Other names

Ubiquitin carboxyl-terminal hydrolase 1Deubiquitinating enzyme 1Ubiquitin-specific-targeting protease 1USP1

Inhibition of the deubiquitinating activity of USP1, leading to the persistent monoubiquitination of substrates like PCNA and FANCD2, which disrupts DNA repair mechanisms and induces synthetic lethality in DNA-repair-deficient cells.