Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the ‘pushmi-pullyu’ effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment. The result is cancer therapeutics that takes advantage of clinical synthetic lethality, resulting in selective tumor cell kill. Here, we review recent considerations related to DNA repair and new DNARi agents and organize those findings to address future directions and clinical opportunities.

维持基因组完整性对于面对内源和外源环境压力时的适应性生存至关重要。癌症和癌症治疗导致基因组稳定性和保真度的丧失，为利用 DNA 损伤和修复之间的关键平衡提供了治疗机会。使用治疗性抑制剂阻止修复并推动受损 DNA 进入细胞周期，体现了受损 DNA 修复的“pushmi-pullyu”效应。DNA 修复抑制剂 (DNARi) 可分为五个生物功能类别：传感器、介质、转换器、效应器和协作器，它们识别 DNA 损伤、传播损伤 DNA 信息、调节细胞周期检查点和改变微环境。其结果是癌症疗法利用了临床合成致死性，从而选择性杀死肿瘤细胞。在这里，我们回顾了最近与 DNA 修复和新 DNARi 药物相关的考虑因素，并整理这些发现以解决未来的方向和临床机会。