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Mol Cell Biol January 1, 2020; 40 (13):
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Nocodazole-Induced Expression and Phosphorylation of Anillin and Other Mitotic Proteins Are Decreased in DNA-Dependent Protein Kinase Catalytic Subunit-Deficient Cells and Rescued by Inhibition of the Anaphase-Promoting Complex/Cyclosome with proTAME but Not Apcin.

Douglas P , Ye R , Radhamani S , Cobban A , Jenkins NP , Bartlett E , Roveredo J , Kettenbach AN , Lees-Miller SP .

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has well-established roles in DNA double-strand break repair, and recently, nonrepair functions have also been reported. To better understand its cellular functions, we deleted DNA-PKcs from HeLa and A549 cells using CRISPR/Cas9. The resulting cells were radiation sensitive, had reduced expression of ataxia-telangiectasia mutated (ATM), and exhibited multiple mitotic defects. Mechanistically, nocodazole-induced upregulation of cyclin B1, anillin, and securin was decreased in DNA-PKcs-deficient cells, as were phosphorylation of Aurora A on threonine 288, phosphorylation of Polo-like kinase 1 (PLK1) on threonine 210, and phosphorylation of targeting protein for Xenopus Klp2 (TPX2) on serine 121. Moreover, reduced nocodazole-induced expression of anillin, securin, and cyclin B1 and phosphorylation of PLK1, Aurora A, and TPX2 were rescued by inhibition of the anaphase-promoting complex/cyclosome (APC/C) by proTAME, which prevents binding of the APC/C-activating proteins Cdc20 and Cdh1 to the APC/C. Altogether, our studies suggest that loss of DNA-PKcs prevents inactivation of the APC/C in nocodazole-treated cells.

PubMed ID: 32284347
PMC ID: PMC7296215
Article link: Mol Cell Biol
Grant support: [+]

Species referenced: Xenopus
Genes referenced: anln atm atr aurka ccdc25 ccnb1 cdc20 cdh1 cdk1 kif15 mcc mtor myt1 plk1 ppp6c prss1 tpx2 wee1

Article Images: [+] show captions
References [+] :
Blackford, ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. 2017, Pubmed