Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, United States.
Department of Genetics and Development, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, United States.
Curr Opin Genet Dev. 2021 Dec;71:171-181. doi: 10.1016/j.gde.2021.08.006. Epub 2021 Sep 25.
CRISPR-dependent genome editing enables the study of genes and mutations on a large scale. Here we review CRISPR-based functional genomics technologies that generate gene knockouts and single nucleotide variants (SNVs) and discuss how their use has provided new important insights into the function of homologous recombination (HR) genes. In particular, we highlight discoveries from CRISPR screens that have contributed to define the response to PARP inhibition in cells deficient for the HR genes BRCA1 and BRCA2, uncover genes whose loss causes synthetic lethality in combination with BRCA1/2 deficiency, and characterize the function of BRCA1/2 SNVs of uncertain clinical significance. Further use of these approaches, combined with next-generation CRISPR-based technologies, will aid to dissect the genetic network of the HR pathway, define the impact of HR mutations on cancer etiology and treatment, and develop novel targeted therapies for HR-deficient tumors.
CRISPR 依赖的基因组编辑使大规模研究基因和突变成为可能。在这里，我们回顾了基于 CRISPR 的功能基因组学技术，这些技术可生成基因敲除和单核苷酸变异 (SNV)，并讨论了它们的使用如何为同源重组 (HR) 基因的功能提供了新的重要见解。特别是，我们强调了 CRISPR 筛选的发现，这些发现有助于定义 HR 基因 BRCA1 和 BRCA2 缺陷细胞对 PARP 抑制的反应，揭示了那些与 BRCA1/2 缺陷相结合导致合成致死的基因，并阐明了 BRCA1/2 SNV 的功能具有不确定的临床意义。进一步使用这些方法，结合下一代基于 CRISPR 的技术，将有助于剖析 HR 途径的遗传网络，确定 HR 突变对癌症病因和治疗的影响，并为 HR 缺陷肿瘤开发新的靶向治疗方法。
