Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
Cell Rep. 2022 Oct 18;41(3):111524. doi: 10.1016/j.celrep.2022.111524.
The metabolic enzyme branched-chain amino acid transaminase 1 (BCAT1) drives cell proliferation in aggressive cancers such as glioblastoma. Here, we show that BCAT1 localizes to mitotic structures and has a non-metabolic function as a mitotic regulator. Furthermore, BCAT1 is required for chromosome segregation in cancer and induced pluripotent stem cells and tumor growth in human cerebral organoid and mouse syngraft models. Applying gene knockout and rescue strategies, we show that the BCAT1 CXXC redox motif is crucial for controlling cysteine sulfenylation specifically in mitotic cells, promoting Aurora kinase B localization to centromeres, and securing accurate chromosome segregation. These findings offer an explanation for the well-established role of BCAT1 in promoting cancer cell proliferation. In summary, our data establish BCAT1 as a component of the mitotic apparatus that safeguards mitotic fidelity through a moonlighting redox functionality.
代谢酶支链氨基酸转氨酶 1（BCAT1）可驱动神经胶质瘤等侵袭性癌症中的细胞增殖。在这里，我们发现 BCAT1 定位于有丝分裂结构，具有作为有丝分裂调节剂的非代谢功能。此外，BCAT1 对于癌症和诱导多能干细胞中的染色体分离以及人脑类器官和小鼠同基因移植模型中的肿瘤生长是必需的。通过应用基因敲除和拯救策略，我们表明 BCAT1 的CXXC 氧化还原模体对于控制有丝分裂细胞中半胱氨酸亚磺酰化至关重要，促进了 Aurora 激酶 B 向着丝粒的定位，并确保了染色体的准确分离。这些发现为 BCAT1 在促进癌细胞增殖中的既定作用提供了一种解释。总之，我们的数据确立了 BCAT1 作为有丝分裂装置的一个组成部分，通过兼职氧化还原功能来保障有丝分裂的保真度。
