Usp1-flox Mouse

Usp1, or ubiquitin-specific protease 1, is a deubiquitinase enzyme. It plays crucial roles in various biological processes, especially those related to DNA repair, cell cycle regulation, and protein stability. It is involved in pathways such as the homologous-recombination repair pathway and is associated with the regulation of key proteins in multiple signaling cascades. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions [1-10].

In BRCA1-deficient tumors, knockdown or inhibition of Usp1 led to replication fork destabilization and decreased cell viability, uncovering a synthetic lethal relationship. The persistence of monoubiquitinated PCNA at the replication fork was the mechanism of cell death in the absence of Usp1 [1]. In cholangiocarcinoma (CCA), Usp1 promotes progression by deubiquitinating PARP1 to prevent its proteasomal degradation [2]. In hepatocellular carcinoma (HCC), Usp1 modulates progression via the Hippo/TAZ axis by enhancing TAZ stability [3]. In muscle during prolonged starvation, Usp1 deubiquitinates Akt to inhibit PI3K-Akt-FoxO signaling [4]. In cancers with DNA damage vulnerabilities, such as BRCA1/2 mutant tumors, inhibition of Usp1 leads to decreased DNA synthesis and S-phase-specific DNA damage, with the accumulation of ubiquitinated PCNA being a key factor [5]. In CD4+ T-cell differentiation, Usp1 promotes Th17-cell differentiation but attenuates Treg-cell differentiation [6]. In adipocyte differentiation, Usp1 enhances the stability of C/EBPβ, accelerating adipogenesis and lipid accumulation [7]. In HCC, inhibition of Usp1 activates ER stress through ubiquitin-protein aggregation, inducing autophagy and apoptosis [8]. In cancer cells, Usp1 regulates MAST1-driven cisplatin-resistance by stabilizing MAST1 [9]. And the USP1 inhibitor KSQ-4279 can overcome PARP inhibitor resistance in homologous recombination-deficient tumors [10].

In conclusion, Usp1 is a multifunctional deubiquitinase. Its functions span across DNA repair, cancer cell progression, metabolic regulation, and immune cell differentiation. Studies using KO/CKO mouse models have revealed its significance in various disease areas, especially in cancers like BRCA1-deficient tumors, cholangiocarcinoma, and hepatocellular carcinoma. These findings offer potential therapeutic strategies, such as targeting Usp1, for treating related diseases.