Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

中文翻译：

---

PP2A 抑制通过纺锤体组装检查点重新激活导致 BRCA2 突变前列腺癌模型的合成致死

BRCA2肿瘤抑制基因的突变与患前列腺癌的风险增加有关。关于 BRCA2 的悖论之一是，它的失活会影响遗传稳定性，并且对细胞和有机体的生存有害，而BRCA2突变的癌细胞会适应这种损害并恶性增殖。通过了解这些适应性机制，可以发现针对BRCA2突变引起的肿瘤的治疗策略。在本研究中，我们对秀丽隐杆线虫 brc-2 ( Cebrc-2 ) 突变体进行了正向遗传合成活力筛选，发现Ceubxn-2失活挽救了Cebrc-2突变体的活力。此外，NSFL1C（CeUBXN-2的哺乳动物直系同源物）的缺失抑制了纺锤体组装检查点（SAC）的激活并促进了BRCA2缺陷细胞的存活。从机制上讲，NSFL1C 招募 USP9X 来抑制 AURKB 的多泛素化，并减少 VCP 从着丝粒中去除 AURKB，这对于 SAC 激活至关重要。SAC 失活在 BRCA2 缺陷型前列腺癌患者中很常见，但 PP2A 抑制剂可以重新激活 SAC 并实现 BRCA2 缺陷型前列腺肿瘤合成致死。我们的研究揭示了BRCA2缺陷型前列腺肿瘤细胞的生存适应机制，并为除了针对DNA损伤修复途径之外探索合成致死抑制剂提供了不同的角度。