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

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.

Automated summary

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.