The BRCA1–PALB2–BRCA2 axis plays essential roles in the cellular response to DNA double-strand breaks (DSB), maintenance of genome integrity, and suppression of cancer development. Upon DNA damage, BRCA1 is recruited to DSBs, where it facilitates end resection and recruits PALB2 and its associated BRCA2 to load the central recombination enzyme RAD51 to initiate homologous recombination (HR) repair. In recent years, several BRCA1-independent mechanisms of PALB2 recruitment have also been reported. Collectively, these available data illustrate a series of hierarchical, context-dependent, and cooperating mechanisms of PALB2 recruitment that is critical for HR and therapy response either in the presence or absence of BRCA1. Here, we review these BRCA1-dependent and independent mechanisms and their importance in DSB repair, cancer development, and therapy. As BRCA1-mutant cancer cells regain HR function, for which PALB2 is generally required, and become resistant to targeted therapies, such as PARP inhibitors, targeting BRCA1-independent mechanisms of PALB2 recruitment represents a potential new avenue to improve treatment of BRCA1-mutant tumors.

中文翻译：

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DNA 损伤反应和癌症中 PALB2–BRCA2–RAD51 的 BRCA1 依赖性和独立招募

BRCA1-PALB2-BRCA2 轴在细胞对 DNA 双链断裂 (DSB) 的反应、维持基因组完整性和抑制癌症发展中发挥着重要作用。DNA 损伤后，BRCA1 被招募到 DSB，促进末端切除，并招募 PALB2 及其相关的 BRCA2 来加载中央重组酶 RAD51，从而启动同源重组 (HR) 修复。近年来，还报道了几种不依赖于 BRCA1 的 PALB2 募集机制。总的来说，这些可用数据说明了 PALB2 募集的一系列分层、上下文相关和协作机制，无论是否存在 BRCA1，这些机制对于 HR 和治疗反应都至关重要。在这里，我们回顾了这些 BRCA1 依赖和独立机制及其在 DSB 修复、癌症发展、和治疗。随着 BRCA1 突变癌细胞恢复 HR 功能（PALB2 通常需要该功能），并对 PARP 抑制剂等靶向治疗产生耐药性，针对 BRCA1 独立的 PALB2 募集机制代表了改善 BRCA1 突变肿瘤治疗的潜在新途径。