Journal
CELL REPORTS
Volume 42, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2023.112215
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Drugs targeting microtubules use the mitotic checkpoint to stop cell proliferation. Prolonged mitotic arrest caused by these drugs leads to a G1 arrest. After treating G1-arrested human cells with nocodazole and observing them for several weeks, it is found that a small fraction of cells escapes the arrest and resumes proliferation. This escape is associated with reduced DNA damage, p21 activation, and increased levels of anti-apoptotic protein Triap1.
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 -ar-rested 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.
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