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A meiotic B-type cyclin selectively drives mitotic progression and fidelity in cancer cells

Kizhedathu, A.; Nguyen, A. C. N.; Yu, C.; Moghareh, S.; Tran, V.; Mousaian, P.; Vertiz, J.; Benavente, C. A.; Huang, L.; Lara-Gonzalez, P.

2026-09-28 cancer biology
10.64898/2026.09.28.754947 bioRxiv
Show abstract

Cell cycle transitions are driven by cyclins in complex with cyclin-dependent kinases (CDK). Here, we demonstrate that cyclin B3, an evolutionarily divergent B-type cyclin previously thought to function exclusively in female meiosis, is expressed in mitotic cells and interacts with both CDK1 and CDK2. We show that cyclin B3-CDK1/2 is essential for timely mitotic progression by ensuring proper chromosome alignment and stable kinetochore-microtubule interactions, while its overexpression accelerates mitosis and improves chromosome alignment kinetics. Through phospho-mass spectrometry, we identify several kinetochore and mitotic spindle components as substrates of cyclin B3-CDK1/2 in mitosis. Notably, cyclin B3 depletion disrupts mitotic progression in most cancer cell lines tested - including colorectal, osteosarcoma, and breast cancer models - while non-transformed cells are largely unaffected. These findings identify cyclin B3-CDK1/2 as a novel driver of mitotic progression and reveal a preferential dependency in a subset of cancer cells that may represent a potential therapeutic vulnerability.

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