Table_1_Yeast as a Model to Unravel New BRCA2 Functions in Cell Metabolism.xlsx

Mutations in BRCA2 gene increase the risk for breast cancer and for other cancer types, including pancreatic and prostate cancer. Since its first identification as an oncosupressor in 1995, the best-characterized function of BRCA2 is in the repair of DNA double-strand breaks (DSBs) by homologous recombination. BRCA2 directly interacts with both RAD51 and single-stranded DNA, mediating loading of RAD51 recombinase to sites of single-stranded DNA. In the absence of an efficient homologous recombination pathway, DSBs accumulate resulting in genome instability, thus supporting tumorigenesis. Yet the precise mechanism by which BRCA2 exerts its tumor suppressor function remains unclear. BRCA2 has also been involved in other biological functions including protection of telomere integrity and stalled replication forks, cell cycle progression, transcriptional control and mitophagy. Recently, we and others have reported a role of BRCA2 in modulating cell death programs through a molecular mechanism conserved in yeast and mammals. Here we hypothesize that BRCA2 is a multifunctional protein which exerts specific functions depending on cell stress response pathway. Based on a differential RNA sequencing analysis carried out on yeast cells either growing or undergoing a regulated cell death process, either in the absence or in the presence of BRCA2, we suggest that BRCA2 causes central carbon metabolism reprogramming in response to death stimuli and encourage further investigation on the role of metabolic reprogramming in BRCA2 oncosuppressive function.

BRCA2基因（BRCA2 gene）的突变可提升乳腺癌及胰腺癌、前列腺癌等多种癌症的患病风险。自1995年该基因首次被鉴定为肿瘤抑制因子（oncosupressor）以来，目前研究最为深入的BRCA2功能是通过同源重组（homologous recombination）修复DNA双链断裂（DNA double-strand breaks, DSBs）。BRCA2可直接与RAD51及单链DNA结合，介导RAD51重组酶加载至单链DNA位点。若缺乏高效的同源重组修复通路，DNA双链断裂会持续积累，导致基因组不稳定，进而促进肿瘤发生。然而，BRCA2发挥肿瘤抑制功能的确切分子机制仍未明确。BRCA2还参与诸多其他生物学过程，包括维持端粒完整性、稳定停滞的复制叉、调控细胞周期进程、转录调控以及线粒体自噬（mitophagy）。近期，本团队与其他研究团队均报道了BRCA2可通过在酵母与哺乳动物中保守的分子机制，调控细胞死亡程序。在此我们提出假说：BRCA2是一类多功能蛋白，其具体功能会因细胞应激反应通路的不同而产生差异。基于对存在或缺失BRCA2的酵母细胞在增殖状态或经历调控性细胞死亡过程中开展的差异RNA测序（differential RNA sequencing）分析，我们认为BRCA2可在死亡刺激下引发中心碳代谢重编程，并呼吁学界进一步探究代谢重编程在BRCA2肿瘤抑制功能中发挥的作用。