Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China.
Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing, China; Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, China.
J Biol Chem. 2024 Oct;300(10):107780. doi: 10.1016/j.jbc.2024.107780. Epub 2024 Sep 12.
Resistance to DNA-damaging agents is a major unsolved challenge for breast cancer patients undergoing chemotherapy. Here, we show that elevated expression of transcriptional repressor GATA binding 1 (TRPS1) is associated with lower drug sensitivity, reduced response rate, and poor prognosis in chemotherapy-treated breast cancer patients. Mechanistically, elevated TRPS1 expression promotes hyperactivity of DNA damage repair (DDR) in breast cancer cells. We provide evidence that TRPS1 dynamically localizes to DNA breaks in a Ku70-and Ku80-dependent manner and that TRPS1 is a new member of the DDR protein family. We also discover that the dynamics of TRPS1 assembly at DNA breaks is regulated by its reversible PARylation in the DDR, and that mutations of the PARylation sites on TRPS1 lead to increased sensitivity to chemotherapeutic drugs. Taken together, our findings provide new mechanistic insights into the DDR and chemoresistance in breast cancer patients and identify TRPS1 as a critical DDR protein. TRPS1 may also be considered as a target to improve chemo-sensitization strategies and, consequently, clinical outcomes for breast cancer patients.
对接受化疗的乳腺癌患者来说，抵抗破坏 DNA 的药物是一个主要的未解决的挑战。在这里，我们表明转录抑制因子 GATA 结合蛋白 1（TRPS1）的高表达与化疗治疗的乳腺癌患者的药物敏感性降低、反应率降低和预后不良有关。在机制上，升高的 TRPS1 表达促进了乳腺癌细胞中 DNA 损伤修复（DDR）的过度活跃。我们提供的证据表明，TRPS1 以依赖 Ku70 和 Ku80 的方式动态定位到 DNA 断裂处，并且 TRPS1 是 DDR 蛋白家族的新成员。我们还发现，TRPS1 在 DNA 断裂处组装的动力学受其在 DDR 中的可逆 PAR 化调节，并且 TRPS1 上 PAR 化位点的突变导致对化疗药物的敏感性增加。综上所述，我们的研究结果为乳腺癌患者的 DDR 和化疗耐药性提供了新的机制见解，并确定 TRPS1 为关键的 DDR 蛋白。TRPS1 也可以被认为是提高化疗增敏策略的靶点，从而改善乳腺癌患者的临床预后。
