USP1, or ubiquitin-specific protease 1, is a deubiquitinase. It plays crucial roles in multiple biological processes by removing ubiquitin chains from target proteins, thus influencing protein stability and function. It is associated with pathways such as DNA repair, Hippo signaling, and PI3K-Akt-FoxO signaling, and is of great biological importance in maintaining normal cellular functions and in disease contexts [1,2,4]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In BRCA1-deficient tumor cells, knockdown or inhibition of USP1 led to replication fork destabilization and decreased cell viability, revealing a synthetic lethal relationship. Persistence of monoubiquitinated PCNA at the replication fork was the cell-death mechanism in the absence of USP1 [1]. In hepatocellular carcinoma (HCC), USP1 depletion affected Hippo signaling activity, and USP1 interacted with TAZ to enhance its stability, promoting HCC progression [2]. In cholangiocarcinoma (CCA), USP1 stabilized PARP1 by deubiquitinating it, and this was necessary for CCA growth and metastasis [3]. In muscle during prolonged starvation, USP1 removed K63-linked polyubiquitin chains on Akt to restrict PI3K-Akt-FoxO signaling [4].

In conclusion, USP1 is a key deubiquitinase involved in DNA repair at replication forks, regulation of Hippo signaling in HCC, stabilization of PARP1 in CCA, and modulation of PI3K-Akt-FoxO signaling in muscle. Studies using KO/CKO mouse models (or equivalent loss-of-function experiments) have revealed its roles in these disease-related biological processes, offering potential therapeutic targets for BRCA1-deficient tumors, HCC, CCA, and potentially other diseases related to abnormal signaling pathways [1-4].

References:

1. Lim, Kah Suan, Li, Heng, Roberts, Emma A, Zheng, Ning, D'Andrea, Alan D. . USP1 Is Required for Replication Fork Protection in BRCA1-Deficient Tumors. In Molecular cell, 72, 925-941.e4. doi:10.1016/j.molcel.2018.10.045. https://pubmed.ncbi.nlm.nih.gov/30576655/

2. Liu, Dongyi, Li, Quanhui, Zang, Yifeng, Yang, Huijie, Ding, Yinlu. 2023. USP1 modulates hepatocellular carcinoma progression via the Hippo/TAZ axis. In Cell death & disease, 14, 264. doi:10.1038/s41419-023-05777-1. https://pubmed.ncbi.nlm.nih.gov/37041150/

3. Zhang, Deng Yong, Zhu, Yan, Wu, Qiong, Kwong, Lawrence N, Lu, Zheng. 2023. USP1 promotes cholangiocarcinoma progression by deubiquitinating PARP1 to prevent its proteasomal degradation. In Cell death & disease, 14, 669. doi:10.1038/s41419-023-06172-6. https://pubmed.ncbi.nlm.nih.gov/37821462/

4. Goldbraikh, Dana, Neufeld, Danielle, Eid-Mutlak, Yara, Parnis, Anna, Cohen, Shenhav. 2020. USP1 deubiquitinates Akt to inhibit PI3K-Akt-FoxO signaling in muscle during prolonged starvation. In EMBO reports, 21, e48791. doi:10.15252/embr.201948791. https://pubmed.ncbi.nlm.nih.gov/32133736/