BRCA1 是一种乳腺癌易感基因，已成为一种中心介质，可将多种信号复合物聚集在一起以响应 DNA 损伤。 BRCA1 的 A、B 和 C 复合物是基于与 BRCA1-C 末端结构域的磷酸化依赖性相互作用而形成的，有助于 BRCA1 在 DNA 修复和细胞周期检查点控制中的作用。然而，它们在 DNA 损伤反应中的功能仍有待充分认识。具体而言，目前尚未对 BRCA1-A、-B 和 -C 复合物在 BRCA1 定位和功能调节中的作用进行系统研究，部分原因是与 CtIP 蛋白丢失相关的细胞致死性，而 CtIP 蛋白是重要的组成部分存在于 BRCA1-C 复合物中。为了系统地研究这些复合物在 DNA 损伤反应中的功能，我们耗尽了每个复合物中的关键成分。我们使用降解标签系统诱导耗尽内源性 CtIP，并获得了一系列 RAP80/FANCJ/CtIP 单、双和三敲除细胞。我们发现，BRCA1-B/FANCJ 和 BRCA1-C/CtIP 的缺失（而非 BRCA1-A/RAP80）会导致细胞增殖减少和对 DNA 损伤的敏感性增加。 BRCA1-C/CtIP 和 BRCA1-A/RAP80 参与 BRCA1 招募到 DNA 损伤位点的过程。然而，BRCA1-A/RAP80 对于损伤诱导的 BRCA1 定位并不是必需的。相反，RAP80/H2AX 和 CtIP 在 BRCA1 招募中具有冗余作用。总而言之，我们的系统分析揭示了 BRCA1-A、-B 和 -C 复合物之间的功能差异，并为这些 BRCA1 相关蛋白复合物在 DNA 损伤反应和 DNA 修复中的作用提供了新的见解。© 2024。 ，获得施普林格自然有限公司的独家许可。

BRCA1, a breast cancer susceptibility gene, has emerged as a central mediator that brings together multiple signaling complexes in response to DNA damage. The A, B, and C complexes of BRCA1, which are formed based on their phosphorylation-dependent interactions with the BRCA1-C-terminal domains, contribute to the roles of BRCA1 in DNA repair and cell cycle checkpoint control. However, their functions in DNA damage response remain to be fully appreciated. Specifically, there has been no systematic investigation of the roles of BRCA1-A, -B, and -C complexes in the regulation of BRCA1 localization and functions, in part because of cellular lethality associated with loss of CtIP protein, which is an essential component in BRCA1-C complex. To systematically investigate the functions of these complexes in DNA damage response, we depleted a key component in each of these complexes. We used the degradation tag system to inducibly deplete endogenous CtIP and obtained a series of RAP80/FANCJ/CtIP single-, double-, and triple-knockout cells. We showed that loss of BRCA1-B/FANCJ and BRCA1-C/CtIP, but not BRCA1-A/RAP80, resulted in reduced cell proliferation and increased sensitivity to DNA damage. BRCA1-C/CtIP and BRCA1-A/RAP80 were involved in BRCA1 recruitment to sites of DNA damage. However, BRCA1-A/RAP80 was not essential for damage-induced BRCA1 localization. Instead, RAP80/H2AX and CtIP have redundant roles in BRCA1 recruitment. Altogether, our systematic analysis uncovers functional differences between BRCA1-A, -B, and -C complexes and provides new insights into the roles of these BRCA1-associated protein complexes in DNA damage response and DNA repair.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.