进化培育了强大的 DNA 损伤反应 (DDR) 机制来对抗 DNA 损伤。然而，这种复杂机制的破坏可能会使细胞过度依赖剩余的功能性但通常不太准确的 DNA 修复途径。这种对易错途径的依赖性增加可能会导致不正确的修复和突变的积累，从而促进基因组不稳定并促进癌症发生和进展的不受控制的细胞增殖特征。基于合成致死（SL）概念的策略通过靶向替代途径来利用癌细胞固有的基因组不稳定性，从而诱导癌细胞选择性死亡。本综述强调了关键 SL 目标结构研究的最新进展。基于结构的方法对 SL 研究的重大贡献强调了它们在表征日益增多的 SL 靶标方面的潜在影响，这主要归功于下一代测序的进步。利用这些方法对于推进精确和个性化的 SL 治疗策略的开发至关重要。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Evolution has fostered robust DNA damage response (DDR) mechanisms to combat DNA lesions. However, disruptions in this intricate machinery can render cells overly reliant on the remaining functional but often less accurate DNA repair pathways. This increased dependence on error-prone pathways may result in improper repair and the accumulation of mutations, fostering genomic instability and facilitating the uncontrolled cell proliferation characteristic of cancer initiation and progression. Strategies based on the concept of synthetic lethality (SL) leverage the inherent genomic instability of cancer cells by targeting alternative pathways, thereby inducing selective death of cancer cells. This review emphasizes recent advancements in structural investigations of pivotal SL targets. The significant contribution of structure-based methodologies to SL research underscores their potential impact in characterizing the growing number of SL targets, largely due to advances in next-generation sequencing. Harnessing these approaches is essential for advancing the development of precise and personalized SL therapeutic strategies.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.