瑞士联邦理工学院Jacob E. Corn课题组在研究中取得进展。他们开发出DNA损伤反应中合成致死性的综合探讨。相关论文于2025年4月9日发表于国际顶尖学术期刊《自然》杂志上。

在这里，研究小组以CRISPR干扰（CRISPRi）筛选为主题，全面绘制所有核心DDR基因在正常人类细胞稳态期间生存所需的遗传相互作用。该课题组捕获了已知的互动，并发现了无数在线可用的新联系。小组确定了两种最强相互作用的分子机制。首先，该课题组发现WDR48与USP1一起抑制FEN1/LIG1缺陷细胞中的PCNA降解。其次，该课题组研究人员发现SMARCAL1和FANCM直接解开富含TA的DNA十字形，防止ERCC1-ERCC4复合体对染色体的灾难性破坏。他们的数据提供了对基因组维持的基本见解，为机制研究DDR因素之间的新联系提供了跳板，并确定了可以在癌症治疗中利用的合成脆弱性。

据悉，DNA损伤反应（DDR）是一个保持基因组稳定性的多方面通路网络。解开这些途径之间互补的相互作用仍然是一个挑战。

附：英文原文

Title: Comprehensive interrogation of synthetic lethality in the DNA damage response

Author: Fielden, John, Siegner, Sebastian M., Gallagher, Danielle N., Schrder, Markus S., Dello Stritto, Maria Rosaria, Lam, Simon, Kobel, Lena, Schlapansky, Moritz F., Jackson, Stephen P., Cejka, Petr, Jost, Marco, Corn, Jacob E.

Issue&Volume: 2025-04-09

Abstract: The DNA damage response (DDR) is a multifaceted network of pathways that preserves genome stability1,2. Unravelling the complementary interplay between these pathways remains a challenge3,4. Here we used CRISPR interference (CRISPRi) screening to comprehensively map the genetic interactions required for survival during normal human cell homeostasis across all core DDR genes. We captured known interactions and discovered myriad new connections that are available online. We defined the molecular mechanism of two of the strongest interactions. First, we found that WDR48 works with USP1 to restrain PCNA degradation in FEN1/LIG1-deficient cells. Second, we found that SMARCAL1 and FANCM directly unwind TA-rich DNA cruciforms, preventing catastrophic chromosome breakage by the ERCC1–ERCC4 complex. Our data yield fundamental insights into genome maintenance, provide a springboard for mechanistic investigations into new connections between DDR factors and pinpoint synthetic vulnerabilities that could be exploited in cancer therapy.

DOI: 10.1038/s41586-025-08815-4

Source: https://www.nature.com/articles/s41586-025-08815-4