BCAT1 redox function maintains mitotic fidelity

• Published in: Cell reports (Cambridge) Vol. 41; no. 3; p. 111524
• Main Authors: Francois, Liliana, Boskovic, Pavle, Knerr, Julian, He, Wei, Sigismondo, Gianluca, Schwan, Carsten, More, Tushar H., Schlotter, Magdalena, Conway, Myra E., Krijgsveld, Jeroen, Hiller, Karsten, Grosse, Robert, Lichter, Peter, Radlwimmer, Bernhard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.10.2022
• Subjects: Amino Acids, Branched-Chain; Animals; Aurora Kinase B; BCAT1; cancer; chromosome segregation; Cysteine; Disease Models, Animal; Humans; metabolism; Mice; mitosis; moonlighting function; Oxidation-Reduction; redox; stem cells; Transaminases; stem cells; chromosome segregation; CP: Cell biology; cancer; metabolism; BCAT1; mitosis; moonlighting function; redox
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •BCAT1 interacts with mitotic spindle and kinetochore proteins•BCAT1 CXXC redox motif is essential for controlling protein oxidation in mitosis•BCAT1 sustains mitotic kinase activity•BCAT1 CXXC motif maintains AURKB centromere localization and mitotic fidelity Francois et al. show that the metabolic enzyme BCAT1 has a moonlighting function in mitosis that requires its redox-active CXXC motif. BCAT1 interacts with components of the spindle and kinetochore, prevents cysteine oxidation, and modulates the activity of mitotic kinases to sustain mitotic fidelity.