利用复制应激反应优化癌症治疗

SCI

12 November 2022

Leveraging the replication stress response to optimize cancer therapy

（Nat Rev Cancer;IF:69.800）

Cybulla E, Vindigni A. Leveraging the replication stress response to optimize cancer therapy. Nat Rev Cancer 2022

Correspondence to：avindigni@wustl.edu

High-fidelity DNA replication is critical for the faithful transmission of genetic information to daughter cells. Following genotoxic stress, specialized DNA damage tolerance pathways are activated to ensure replication fork progression. These pathways include translesion DNA synthesis, template switching and repriming. In this Review, we describe how DNA damage tolerance pathways impact genome stability, their connection with tumorigenesis and their effects on cancer therapy response. We discuss recent findings that single- strand DNA gap accumulation impacts chemoresponse and explore a growing body of evidence that suggests that different DNA damage tolerance factors, including translesion synthesis polymerases, template switching proteins and enzymes affecting single- stranded DNA gaps, represent useful cancer targets. We further outline how the consequences of DNA damage tolerance mechanisms could inform the discovery of new biomarkers to refine cancer therapies. 

高保真DNA复制对于将遗传信息忠实地传递到子细胞至关重要。在基因毒性应激之后，专门的DNA损伤耐受途径被激活以确保复制叉进展。这些途径包括跨病变DNA合成、模板切换和再修饰。在本综述中，我们描述了DNA损伤耐受途径如何影响基因组稳定性，它们与肿瘤发生的联系以及它们对癌症治疗反应的影响。我们讨论了单链DNA间隙积累影响化学反应的最新发现，并探索了不同的DNA损伤耐受因子，包括跨病变合成聚合酶，模板切换蛋白和影响单链DNA间隙的酶，越来越多的证据表明这些是有用的癌症靶点。我们进一步概述了DNA损伤耐受机制如何为发现新的生物标志物提供信息，以改进癌症疗法。