Usp45-KO Mouse

Usp45, a ubiquitin-specific protease, functions as a deubiquitinating enzyme, removing ubiquitin molecules from target proteins. This activity is involved in multiple biological processes such as DNA damage repair, cell migration, and autophagy regulation. It is also associated with pathways related to tumorigenesis and retinal development [3,4,5,7].

In the context of serous ovarian cancer, knockdown of MYH10, which combines with MYH9 to recruit USP45, suppressed cancer cell proliferation, migration, invasion, metastasis, and cisplatin resistance, suggesting that USP45 promotes carcinogenesis, progression, and cisplatin resistance in this cancer type [1]. Pan-cancer analysis showed that USP45 is upregulated in most tumors, negatively correlated with patient survival, and related to mRNA methylation, tumor heterogeneity, and stemness [2]. In esophageal cancer, it acts as an oncogene regulating cell proliferation [6]. Inhibition of USP45 by a natural small molecule suppressed cancer cell stemness and drug resistance in cervical tumors [8]. In Leber congenital amaurosis, biallelic mutations in USP45 were associated with the disease, and knockout mice showed abnormal electroretinography responses similar to patients, indicating its importance in photoreceptor function [5].

In summary, USP45 is a crucial deubiquitinating enzyme involved in DNA repair, cell migration, and autophagy. Its dysregulation is associated with various diseases, especially cancers and Leber congenital amaurosis. Studies using gene-knockout models, like the Usp45 knockout mice in the context of Leber congenital amaurosis, have been instrumental in revealing its role in these disease conditions.

References:

1. Liu, Longyang, Chen, Chunlin, Liu, Ping, Zeng, Zhaoyang, Fang, Weiyi. 2023. MYH10 Combines with MYH9 to Recruit USP45 by Deubiquitinating Snail and Promotes Serous Ovarian Cancer Carcinogenesis, Progression, and Cisplatin Resistance. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 10, e2203423. doi:10.1002/advs.202203423. https://pubmed.ncbi.nlm.nih.gov/36929633/

2. Li, Kai, Wang, Qian, Bian, Hua, Zhao, Xulin, Gong, Pengju. 2022. Comprehensive Analysis Reveals USP45 as a Novel Putative Oncogene in Pan-Cancer. In Frontiers in molecular biosciences, 9, 886904. doi:10.3389/fmolb.2022.886904. https://pubmed.ncbi.nlm.nih.gov/35836933/

3. Perez-Oliva, Ana B, Lachaud, Christophe, Szyniarowski, Piotr, Rouse, John, Alessi, Dario R. 2014. USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses. In The EMBO journal, 34, 326-43. doi:10.15252/embj.201489184. https://pubmed.ncbi.nlm.nih.gov/25538220/

4. Conte, Claudia, Griffis, Eric R, Hickson, Ian, Perez-Oliva, Ana B. 2018. USP45 and Spindly are part of the same complex implicated in cell migration. In Scientific reports, 8, 14375. doi:10.1038/s41598-018-32685-8. https://pubmed.ncbi.nlm.nih.gov/30258100/

5. Yi, Zhen, Ouyang, Jiamin, Sun, Wenmin, Wang, Panfeng, Zhang, Qingjiong. 2018. Biallelic mutations in USP45, encoding a deubiquitinating enzyme, are associated with Leber congenital amaurosis. In Journal of medical genetics, 56, 325-331. doi:10.1136/jmedgenet-2018-105709. https://pubmed.ncbi.nlm.nih.gov/30573563/

6. Li, Kai, Wang, Qian, Bian, Hua. 2023. USP45 acts as an oncogene to regulate the proliferation of esophageal cancer cells. In Genes & diseases, 11, 101135. doi:10.1016/j.gendis.2023.101135. https://pubmed.ncbi.nlm.nih.gov/38868575/

7. Lin, Yuchieh Jay, Huang, Li-Ting, Ke, Po-Yuan, Chen, Guang-Chao. 2025. The deubiquitinase USP45 inhibits autophagy through actin regulation by Coronin 1B. In The Journal of cell biology, 224, . doi:10.1083/jcb.202407014. https://pubmed.ncbi.nlm.nih.gov/40067150/

8. Tu, Xiao, Li, Chuncheng, Sun, Wen, Ding, Xiaoling, Huang, Zhen. 2023. Suppression of Cancer Cell Stemness and Drug Resistance via MYC Destabilization by Deubiquitinase USP45 Inhibition with a Natural Small Molecule. In Cancers, 15, . doi:10.3390/cancers15030930. https://pubmed.ncbi.nlm.nih.gov/36765885/