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This study shows that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), thereby contributing to chemoresistance. USP25 deubiquitinates SHLD2 at K64, strengthening SHLD2 binding to REV7 and enhancing NHEJ. USP25 loss reduces NHEJ-mediated repair and class switch recombination in mice, while USP25 overexpression in colon cancer promotes resistance; USP25 inhibition sensitizes cells to IR, 5-Fu, and cisplatin. 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Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 atthe K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ-mediated DNA repair and reduces class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5-Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induceschemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25-SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector ofSHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.  \n1. Introduction  \nThe DNA damage response (DDR) system is critical to maintain genomic integrity and guard against DNA damage. Dysfunction in the DDR pathway results in genomic instability which is a key driving force to the initiation and progression of tumorigenesis. DNA double-strand breaks (DSBs) are the most lethal lesions, which can trigger a series of cellular DNA damage responses. [1,2] DSBs are repaired by two major pathways, namely homologous recombination (HR) and nonhomologous end joining (NHEJ) . The NHEJ pathway repairs 75% of DSBsin proliferating cells and occurs throughout the cell cycle. [3] Shielding DNA ends is a central process in initiating the NHEJ repair of DSBs. Recent reports have identified the shieldin complex as a new effector of 53BP1-associated activities that facilitates NHEJ repair and limits DNA end  \nY. Li, L. Li, X. Wang, Y. Yang, Y. Zhou, J. Zhang, L. Wang, Z. Jiang, C. Wu, J. Yuan  \nMedical Innovation Center Shanghai East Hospital School of Medicine Tongji University Shanghai 200120, China  \nE-mail: [1400611@tongji.edu.cn](1400611@tongji.edu.cn); [yuanjian229@tongji.edu.cn](yuanjian229@tongji.edu.cn)  \nY. Li, L. Li, Y. Chen, C. Wu, J. Yuan Cancer Center  \nTongji University School of Medicine Shanghai 200331, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202403485](https://doi.org/10.1002/advs.202403485)[ ](https://doi.org/10.1002/advs.202403485)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202403485  \nY. Li, X. Wang, Y. Yang, Y. Zhou, J. Zhang, L. Wang, Z. Jiang, Y. Chen, J. Yuan  \nDepartment of Biochemistry and Molecular Biology Tongji University School of Medicine  \nShanghai 200331, China  \nF. Zhao  \nCollege of Biology Hunan University Changsha 410082, China  \nY. Zhang  \nDepartment of General Surgery and Colorectal Surgery Shanghai East Hospital  \nTongji University School of Medicine Shanghai 200120, China  \nY. Chen  \nTranslational Research Institute of Brain and Brain-Like Intelligence Shanghai Fourth People’s Hospital  \nScho","cbCaihm0467WQOgi","https://ap.wps.com/l/cbCaihm0467WQOgi","pdf",7238223,17,"English","# Introduction\n## USP25–SHLD2 axis in DNA end protection and NHEJ\n## Post-translational modifications (PTMs) in DDR and therapy response\n## Study focus and rationale","[{\"question\":\"Which protein regulates USP25 levels and what is its effect?\",\"answer\":\"TRIM25 is identified as an E3 ligase that degrades USP25. Reducing TRIM25 increases USP25 levels and induces chemoresistance in colon cancer cells.\"}]","USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer | PDF",1790032168,43]