On May 27th, researchers Yuan Jian and Li Yunhui from Tongji University School of Medicine published a groundbreaking research paper titled "USP25 Elevates SHLD2-Mediated DNA Double-Strand Break Repair and Regulates Chemoresponse in Cancer" in the journal "ADVANCED SCIENCE" (impact factor: 15.1). The study proposed a mechanistic model wherein USP25 deubiquitinates and modifies SHLD2 at the K64 site, thereby promoting non-homologous end joining (NHEJ) repair, consequently reducing the chemical sensitivity of cancer cells. Furthermore, the researchers developed peptides based on disrupting the USP25-SHLD2 interaction strategy, demonstrating that the combination of peptides with chemotherapy drugs improved the killing efficiency of colorectal cancer cells and patient-derived xenograft (PDX) models. These findings suggest a potential therapeutic strategy to enhance chemosensitivity and achieve better outcomes.

The DNA damage response (DDR) system is crucial for maintaining genome integrity and preventing DNA damage. Dysfunction in DDR pathways leads to genomic instability, a key driver of tumor initiation and progression. DNA double-strand breaks (DSBs) are the most lethal lesions, triggering a series of cellular DNA damage responses. DSBs are repaired through two main pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). NHEJ repairs 75% of DSBs in proliferating cells and occurs throughout the cell cycle. Shieldin complex has been identified as a new effector of 53BP1-related activities that promote NHEJ repair and limit DNA end resection. SHLD2, a crucial regulator in the shieldin complex, is essential for promoting NHEJ and class switch recombination (CSR). However, little is known about the regulatory mechanisms controlling SHLD2 activity.

Post-translational modifications (PTMs) play a crucial role in regulating protein function. Many PTMs of key regulators in the NHEJ pathway have been implicated in tumorigenesis and cancer therapy. Specifically, ATM phosphorylation of the S/T-Q site at the N-terminus of 53BP1 is essential for DNA end protection and immunoglobulin class switch recombination (CSR), promoting its interaction with RIF1, activating NHEJ repair, and cancer cell survival. Additionally, RNF168-mediated ubiquitination of K1268 on 53BP1 is essential for NHEJ repair, maintaining genome stability, and radiation sensitivity. However, PTMs regulating SHLD2 remain poorly characterized.

In this study, it was demonstrated that the deubiquitinase USP25 promotes non-homologous end joining (NHEJ), thereby enhancing cancer chemoresistance. The results showed that USP25 deubiquitinates SHLD2 at the K64 site, enhancing its binding to REV7 and promoting NHEJ. Furthermore, USP25 deficiency impaired NHEJ-mediated DNA repair and reduced class switch recombination (CSR) in USP25-deficient mice. USP25 is overexpressed in a subset of colorectal cancers. Depletion of USP25 sensitized colorectal cancer cells to IR, 5-Fu, and cisplatin. TRIM25 was also identified as an E3 ligase responsible for degrading USP25. Downregulation of TRIM25 led to increased levels of USP25, inducing chemoresistance in colorectal cancer cells. Finally, a peptide disrupting the USP25-SHLD2 interaction was successfully identified in PDX models, impairing NHEJ and increasing sensitivity to chemotherapy. Overall, these findings reveal USP25 as a key effector regulating the SHLD2-mediated NHEJ repair pathway and suggest its potential as a target for cancer therapy.

In conclusion, the study proposes a mechanistic model wherein USP25 deubiquitinates and modifies SHLD2 at the K64 site, promoting NHEJ repair and reducing the chemical sensitivity of cancer cells. Subsequently, researchers developed peptides based on disrupting the USP25-SHLD2 interaction strategy, demonstrating that the combination of peptides with chemotherapy drugs improved the killing efficiency of colorectal cancer cells and PDX models. This suggests a potential therapeutic strategy to enhance chemosensitivity and achieve better outcomes.

In conjunction with the research study, all peptides were synthesized by SBS Genetech Co., Ltd. (Beijing, China) and were of high purity (>95%), as determined by high-pressure liquid chromatography. Since 2000, SBS Genetech has been at the forefront of providing solutions in life sciences. We offer safer, superior quality, and more cost-effective products to preeminent researchers in more than 60 countries, empowering them to make new discoveries in biology. Our products have been widely utilized in academic research, with results often published in leading academic journals like Science, Cell, Cancer Cell, and Cell Metabolism. We firmly believe that through continuous innovation and research, we will continually infuse new vitality and possibilities into the field of life sciences.