Research ArticleDNA damage

Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at Ser16 to trigger its nuclear localization

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Science Signaling  14 Apr 2015:
Vol. 8, Issue 372, pp. ra35
DOI: 10.1126/scisignal.aaa0441

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Sending OTUB1 to the nucleus for DNA damage repair

Without the ability to repair DNA damage, genomic instability occurs, which can lead to cell death or cancer. OTUB1 is an enzyme that either removes ubiquitin that has been covalently attached to target proteins or prevents protein ubiquitylation by inhibiting ubiquitin-conjugating enzymes and functions in both the cytosol and nucleus. In the nucleus, OTUB1 functions in DNA repair. Herhaus et al. found that the kinase CK2 phosphorylated OTUB1, enabling its nuclear translocation in cells. Mutating the CK2 phosphorylation site on OTUB1 or pharmacologically inhibiting CK2 impaired DNA repair in cells exposed to ionizing radiation, which causes DNA damage and is used therapeutically to kill cancer cells. These findings may be exploited to decrease a cancer cell’s ability to tolerate radiation therapy.


The deubiquitylating enzyme OTUB1 is present in all tissues and targets many substrates, in both the cytosol and nucleus. We found that casein kinase 2 (CK2) phosphorylated OTUB1 at Ser16 to promote its nuclear accumulation in cells. Pharmacological inhibition or genetic ablation of CK2 blocked the phosphorylation of OTUB1 at Ser16, causing its nuclear exclusion in various cell types. Whereas we detected unphosphorylated OTUB1 mainly in the cytosol, we detected Ser16-phosphorylated OTUB1 only in the nucleus. In vitro, Ser16-phosphorylated OTUB1 and nonphosphorylated OTUB1 exhibited similar catalytic activity, bound K63-linked ubiquitin chains, and interacted with the E2 enzyme UBE2N. CK2-mediated phosphorylation and subsequent nuclear localization of OTUB1 promoted the formation of 53BP1 (p53-binding protein 1) DNA repair foci in the nucleus of osteosarcoma cells exposed to ionizing radiation. Our findings indicate that the activity of CK2 is necessary for the nuclear translocation and subsequent function of OTUB1 in DNA damage repair.

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