Jordan Matthew R, Mendoza-Munoz Pamela L, Pawelczak Katherine S, Turchi John J
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.
NERx BioSciences, Indianapolis, IN, United States.
DNA Repair (Amst). 2025 May;149:103841. doi: 10.1016/j.dnarep.2025.103841. Epub 2025 May 2.
DNA damage occurs from both endogenous and exogenous sources and DNA damaging agents are a mainstay in cancer therapeutics. DNA damage sensors (DDS) are proteins that recognize and bind to unique DNA structures that arise from direct DNA damage or replication stress and are the first step in the DNA damage response (DDR). DNA damage sensors are responsible for recruiting transducer proteins that signal downstream DNA repair pathways. As the initiating proteins, DDS are excellent candidates for anti-cancer drug targeting to limit DDR activation. Here, we review four major DDS: PARP1, RPA, Ku, and the MRN complex. We briefly describe the cellular DDS functions before analyzing the structural mechanisms of DNA damage sensing. Lastly, we examine the current state of the field towards inhibiting each DDS for anti-cancer therapeutics and broadly discuss the therapeutic potential for DDS targeting.
DNA损伤可源于内源性和外源性因素，DNA损伤剂是癌症治疗的主要手段。DNA损伤传感器（DDS）是一类蛋白质，它们能够识别并结合由直接DNA损伤或复制应激产生的独特DNA结构，是DNA损伤反应（DDR）的第一步。DNA损伤传感器负责招募向下游DNA修复途径发出信号的转导蛋白。作为起始蛋白，DDS是抗癌药物靶向作用以限制DDR激活的极佳候选对象。在此，我们综述四种主要的DDS：PARP1、RPA、Ku和MRN复合物。在分析DNA损伤传感的结构机制之前，我们简要描述细胞DDS的功能。最后，我们研究针对抗癌治疗抑制每种DDS的领域现状，并广泛讨论靶向DDS的治疗潜力。
