Whalen Jenna M, Earley Jillian, Wisniewski Christi, Mercurio Arthur M, Cantor Sharon B
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Nat Cancer. 2025 Feb;6(2):278-291. doi: 10.1038/s43018-024-00902-1. Epub 2025 Jan 21.
Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex-which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks. The sensitivity is caused by hyper-resection of nicks into extensive single-stranded regions that trigger cell death. Based on these findings and that nicks limit tumor formation in mice, we propose nickases as a tool for personalized medicine. Moreover, our findings indicate that restricting nick expansion is a critical function of the 53BP1-Shieldin complex.
缺乏BRCA1和BRCA2（BRCA）遗传性乳腺癌基因的肿瘤对抗癌治疗表现出更高的敏感性，例如对聚（ADP - 核糖）聚合酶1（PARP1）抑制剂。然而，当产生耐药性时，却缺乏有效的治疗方法。利用CRISPR技术，我们发现通过缺失与PARP抑制剂耐药性相关的53BP1 - Shieldin复合物，增加BRCA1缺陷细胞中的DNA末端切除来增强同源重组，也会提高对DNA切口的敏感性。这种敏感性是由切口过度切除形成广泛的单链区域从而触发细胞死亡所导致的。基于这些发现以及切口限制小鼠肿瘤形成这一事实，我们提出将切口酶作为个性化医疗的一种工具。此外，我们的研究结果表明，限制切口扩展是53BP1 - Shieldin复合物的一项关键功能。
