Citations 2
Phosphatidylinositol 3-phosphate promotes 53BP1 condensate-like assembly at DNA double-strand breaks
Xiong, Nan, Xu, Xuanqi, Xie, Yawen, Liang, Shikang , Liu, Yang, Yu, Cheng‐han , Mer, Georges , Huen, Michael Shing Yan, Xiong, Nan, Cui, Gaofeng , Ti, Shih-Chieh , Draviam, Viji M.
No container title available | April 22, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
53BP1 nuclear bodies are dynamic structures with properties resembling biomolecular condensates, but the molecular determinants that govern 53BP1 higher-order assembly at DNA double-strand breaks (DSBs) remain to be established. Here, we show that 53BP1 condensation is stimulated by phosphatidylinositol 3-phosphate (PI(3)P) in vitro through a highly specific interaction with its C-terminal tandem BRCT domain (tBRCT). Consequently, mutational inactivation of the 53BP1 tBRCT domain compromised PI(3)P binding and suppressed 53BP1 optodroplet formation in vivo. We further show that rapid 53BP1 clustering following DNA damage precedes its stable assembly on DSB-flanking chromatin, requires its tBRCT, and is suppressed by sequestration of nuclear PI(3)P. Taken together, our findings identify PI(3)P binding as a mechanism that promotes the formation and maturation of 53BP1 condensate-like assemblies on damaged chromatin.
USP25 Elevates SHLD2‐Mediated DNA Double‐Strand Break Repair and Regulates Chemoresponse in Cancer
Li, Yunhui , Li, Lei , Wang, Xinshu , Yang, Yuntong , Zhou, Yujuan, Zhang, Jiyuan , Wang, Li , Jiang, Zeshan, Zhang, Tingting , Wang, Ping , Mao, Zhiyong , Liang, Shikang , Yuan, Jian , Mao, Zhiyong , Zhao, Fei , Zhang, Yuanyuan , Chen, Yuping , Wu, Chenming , Li, Lian , Zhu, Wei‐Guo , Xu, Xingzhi , Lou, Zhenkun , Yuan, Jian
Advanced Science | May 28, 2024 | Volume: 11 | Issue: 28 | Pages: No page available
AbstractDNA damage plays a significant role in the tumorigenesis and progression of the disease. 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 at the 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 induces chemoresistance 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 of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.