Triap1 upregulation promotes escape from mitotic-slippage-induced G1 arrest

• DOI: 10.1016/j.celrep.2023.112215
• Publication Date: 2023-03-13T18:38:43Z
• Authors: Mattia Pavani; Elena Chiroli; Camilla Cancrini; Fridolin Gross; Paolo Bonaiuti; Stefano Villa; Fabio Giavazzi; Vittoria Matafora; Angela Bachi; Luca L. Fava; Tiziana Lischetti; Andrea Ciliberto
• Keywords: CP: Cell biology; CP: Molecular biology; cell cycle; microtubule targeting drugs; mitosis; sublethal caspase activation; QH301-705.5; Nocodazole; CP: Cell biology; G1 Phase; Intracellular Signaling Peptides and Proteins; Humans; Mitosis; CP: Molecular biology; Apoptosis; Biology (General); Up-Regulation; Cell Proliferation

Drugs targeting microtubules rely on the mitotic checkpoint to arrest cell proliferation. The prolonged mitotic arrest induced by such drugs is followed by a G1 arrest. Here, we follow for several weeks the fate of G1-arrested human cells after treatment with nocodazole. We find that a small fraction of cells escapes from the arrest and resumes proliferation. These escaping cells experience reduced DNA damage and p21 activation. Cells surviving treatment are enriched for anti-apoptotic proteins, including Triap1. Increasing Triap1 levels allows cells to survive the first treatment with reduced DNA damage and lower levels of p21; accordingly, decreasing Triap1 re-sensitizes cells to nocodazole. We show that Triap1 upregulation leads to the retention of cytochrome c in the mitochondria, opposing the partial activation of caspases caused by nocodazole. In summary, our results point to a potential role of Triap1 upregulation in the emergence of resistance to drugs that induce prolonged mitotic arrest.