Coleman KE, Yin Y, Lui SKL, Keegan S, Fenyo D, Smith DJ, et al. USP1-trapping lesions as a source of DNA replication stress and genomic instability. Nature Communications. 2022;13:1740. https://doi.org/10.1038/s41467-022-29369-3.
Article CAS PubMed PubMed Central Google Scholar
Nijman SM, Huang TT, Dirac AM, Brummelkamp TR, Kerkhoven RM, D’Andrea AD, et al. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Molecular Cell. 2005;17:331–9. https://doi.org/10.1016/j.molcel.2005.01.008.
Article CAS PubMed Google Scholar
Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, et al. Deubiquitination of FANCD2 is required for DNA crosslink repair. Mol Cell. 2007;28:798–809. https://doi.org/10.1016/j.molcel.2007.09.020.
Article CAS PubMed PubMed Central Google Scholar
Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, et al. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007;28:786–97. https://doi.org/10.1016/j.molcel.2007.09.031.
Article CAS PubMed Google Scholar
Liang F, Miller AS, Longerich S, Tang C, Maranon D, Williamson EA, et al. DNA requirement in FANCD2 deubiquitination by USP1-UAF1-RAD51AP1 in the Fanconi anemia DNA damage response. Nature Communications. 2019;10:2849. https://doi.org/10.1038/s41467-019-10408-5.
Article CAS PubMed PubMed Central Google Scholar
Rennie ML, Arkinson C, Chaugule VK, Walden H. Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Sci Adv. 2022;8:eabq6353. https://doi.org/10.1126/sciadv.abq6353.
Article CAS PubMed PubMed Central Google Scholar
Cadzow L, Brenneman J, Tobin E, Sullivan P, Nayak S, Ali JA, et al. The USP1 inhibitor KSQ-4279 overcomes PARP inhibitor resistance in homologous recombination-deficient tumors. Cancer Res. 2024;84:3419–34. https://doi.org/10.1158/0008-5472.Can-24-0293.
Article CAS PubMed PubMed Central Google Scholar
Korenev G, Yakukhnov S, Druk A, Golovina A, Chasov V, Mirgayazova R, et al. USP7 inhibitors in cancer immunotherapy: current status and perspective. Cancers. 2022;14:5539.
Article CAS PubMed PubMed Central Google Scholar
Keijzer N, Sakoltchik J, Majumder K, van Lil N, El Oualid F, Fish A, et al. USP1/UAF1 targets polyubiquitinated PCNA with an exo-cleavage mechanism that can temporarily enrich for monoubiquitinated PCNA. Nat Commun. 2025;16:6991. https://doi.org/10.1038/s41467-025-61768-0.
Article CAS PubMed PubMed Central Google Scholar
Ryu E, Yoo J, Kang M-S, Ha NY, Jang Y, Kim J, et al. ATAD5 functions as a regulatory platform for Ub–PCNA deubiquitination. Proc Natl Acad Sci USA. 2024;121:e2315759121. https://doi.org/10.1073/pnas.2315759121.
Article CAS PubMed PubMed Central Google Scholar
Dharadhar S, Clerici M, van Dijk WJ, Fish A, Sixma TK. A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme. J Struct Biol. 2016;196:437–47. https://doi.org/10.1016/j.jsb.2016.09.011.
Article CAS PubMed PubMed Central Google Scholar
Li H, Lim Kah S, Kim H, Hinds Thomas R, Jo U, Mao H, et al. Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20. Molecular Cell. 2016;63:249 – 60. https://doi.org/10.1016/j.molcel.2016.05.031.
Dharadhar S, van Dijk WJ, Scheffers S, Fish A, Sixma TK. Insert L1 is a central hub for allosteric regulation of USP1 activity. EMBO Rep. 2021;22:e51749. https://doi.org/10.15252/embr.202051749.
Article CAS PubMed PubMed Central Google Scholar
Foster BM, Wang Z, Schmidt CK. DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability. Biochem J. 2024;481:515–45. https://doi.org/10.1042/bcj20230284.
Article CAS PubMed PubMed Central Google Scholar
Xu X, Guo R, Xu D. The emergence of a unified mechanism in the Fanconi anemia pathway. Genome Instability Disease. 2021;2:281–91. https://doi.org/10.1007/s42764-021-00053-y.
Arkinson C, Chaugule VK, Toth R, Walden H. Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1. Life Sci Alliance. 2018;1:e201800162. https://doi.org/10.26508/lsa.201800162.
Article PubMed PubMed Central Google Scholar
Yin J, Schoeffler AJ, Wickliffe K, Newton K, Starovasnik MA, Dueber EC, et al. Structural insights into WD-Repeat 48 activation of Ubiquitin-Specific protease 46. Structure. 2015;23:2043–54. https://doi.org/10.1016/j.str.2015.08.010.
Article CAS PubMed Google Scholar
Li H, Lim KS, Kim H, Hinds TR, Jo U, Mao H, et al. Allosteric activation of Ubiquitin-Specific proteases by β-Propeller proteins UAF1 and WDR20. Mol Cell. 2016;63:249–60. https://doi.org/10.1016/j.molcel.2016.05.031.
Article CAS PubMed PubMed Central Google Scholar
Rennie ML, Arkinson C, Chaugule VK, Toth R, Walden H. Structural basis of FANCD2 deubiquitination by USP1-UAF1. bioRxiv. 2020:2020.12.05.412924. https://doi.org/10.1101/2020.12.05.412924.
Chen S, Liu Y, Zhou H. Advances in the development Ubiquitin-Specific peptidase (USP) inhibitors. Int J Mol Sci. 2021;22:4546. https://www.mdpi.com/1422-0067/22/9/4546.
Article CAS PubMed PubMed Central Google Scholar
Gao H, Xi Z, Dai J, Xue J, Guan X, Zhao L, et al. Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options. Mol Cancer. 2024;23:88. https://doi.org/10.1186/s12943-024-02005-y.
Article PubMed PubMed Central Google Scholar
Zhu H, Zhang T, Wang F, Yang J, Ding J. Structural insights into the activation of USP46 by WDR48 and WDR20. Cell Discov. 2019;5:34. https://doi.org/10.1038/s41421-019-0102-1.
Article CAS PubMed PubMed Central Google Scholar
Kim Y, Ha NY, Kang MS, Ryu E, Yi G, Yoo J, et al. ATAD5-BAZ1B interaction modulates PCNA ubiquitination during DNA repair. Nat Commun. 2024;15:10496. https://doi.org/10.1038/s41467-024-55005-3.
Article CAS PubMed PubMed Central Google Scholar
Chen J, Dexheimer TS, Ai Y, Liang Q, Villamil MA, Inglese J, et al. Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem Biol. 2011;18:1390–400. https://doi.org/10.1016/j.chembiol.2011.08.014.
Article CAS PubMed PubMed Central Google Scholar
Mistry H, Hsieh G, Buhrlage SJ, Huang M, Park E, Cuny GD, et al. Small-molecule inhibitors of USP1 target ID1 degradation in leukemic cells. Mol Cancer Ther. 2013;12:2651–62. https://doi.org/10.1158/1535-7163.Mct-13-0103-t.
Article CAS PubMed PubMed Central Google Scholar
Torrado C, Ashton NW, D’Andrea AD, Yap TA. USP1 inhibition: a journey from target discovery to clinical translation. Pharmacol Ther. 2025;271:108865. https://doi.org/10.1016/j.pharmthera.2025.108865.
Article CAS PubMed Google Scholar
Yap TA, Lakhani NJ, Patnaik A, Lee EK, Gutierrez M, Moore KN, et al. First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with Olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations. J Clin Oncol. 2024;42:3005. https://doi.org/10.1200/JCO.2024.42.16_suppl.3005.
Comments (0)