所有生物都具有管理DNA修复和相关DNA损伤响应（DDR）过程的分子机制。由于与人类疾病特别是癌症的相关性，这些机制已得到广泛研究，但仍在发现新的DNA修复和/或DDR因子以及它们之间的功能相互作用。CRISPR技术和基于CRISPR的基因筛查的出现，使得可以进行基因-基因和基因-药物相互作用的基因组规模分析，从而为不同DDR缺陷遗传背景和病理情况下的细胞过程提供新的见解。在本综述中，我们讨论了CRISPR-Cas遗传筛查方法的机制基础，并描述了它们如何为我们了解DNA修复和DDR途径做出贡献。我们讨论了DNA修复途径如何被调节，并识别和表征它们之间的交互作用。我们还强调了CRISPR与识别新的癌症治疗策略以及在理解、克服甚至利用癌症药物耐药性方面的研究的影响，例如在PARP抑制、同源重组缺陷和/或复制应激等方面的应用。最后，我们推荐DDR CRISPR筛查门户网站（DDRcs），其中我们收集并再分析了CRISPR筛查研究的数据，并提供了一个系统探索它们的工具。 © 2023. Springer Nature Limited.

All organisms possess molecular mechanisms that govern DNA repair and associated DNA damage response (DDR) processes. Owing to their relevance to human disease, most notably cancer, these mechanisms have been studied extensively, yet new DNA repair and/or DDR factors and functional interactions between them are still being uncovered. The emergence of CRISPR technologies and CRISPR-based genetic screens has enabled genome-scale analyses of gene-gene and gene-drug interactions, thereby providing new insights into cellular processes in distinct DDR-deficiency genetic backgrounds and conditions. In this Review, we discuss the mechanistic basis of CRISPR-Cas genetic screening approaches and describe how they have contributed to our understanding of DNA repair and DDR pathways. We discuss how DNA repair pathways are regulated, and identify and characterize crosstalk between them. We also highlight the impacts of CRISPR-based studies in identifying novel strategies for cancer therapy, and in understanding, overcoming and even exploiting cancer-drug resistance, for example in the contexts of PARP inhibition, homologous recombination deficiencies and/or replication stress. Lastly, we present the DDR CRISPR screen (DDRcs) portal , in which we have collected and reanalysed data from CRISPR screen studies and provide a tool for systematically exploring them.© 2023. Springer Nature Limited.