Title

Deoxycytidine kinase regulates the G2/M checkpoint through interaction with cyclin-dependent kinase 1 in response to DNA damage

Authors

Authors

C. Y. Yang; M. Lee; J. W. Hao; X. L. Cui; X. J. Guo; C. Smal; F. Bontemps; S. M. Ma; X. D. Liu; D. Engler; W. B. Parker;B. Xu

Comments

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Abbreviated Journal Title

Nucleic Acids Res.

Keywords

IONIZING IRRADIATION; MITOTIC INHIBITOR; S-PHASE; ATM; PROTEIN; PHOSPHORYLATION; ACTIVATION; IDENTIFICATION; LYMPHOCYTES; INVOLVEMENT; Biochemistry & Molecular Biology

Abstract

Deoxycytidine kinase (dCK) is a rate limiting enzyme critical for phosphorylation of endogenous deoxynucleosides for DNA synthesis and exogenous nucleoside analogues for anticancer and antiviral drug actions. dCK is activated in response to DNA damage; however, how it functions in the DNA damage response is largely unknown. Here, we report that dCK is required for the G2/M checkpoint in response to DNA damage induced by ionizing radiation (IR). We demonstrate that the ataxia-telangiectasia-mutated (ATM) kinase phosphorylates dCK on Serine 74 to activate it in response to DNA damage. We further demonstrate that Serine 74 phosphorylation is required for initiation of the G2/M checkpoint. Using mass spectrometry, we identified a protein complex associated with dCK in response to DNA damage. We demonstrate that dCK interacts with cyclin-dependent kinase 1 (Cdk1) after IR and that the interaction inhibits Cdk1 activity both in vitro and in vivo. Together, our results highlight the novel function of dCK and provide molecular insights into the G2/M checkpoint regulation in response to DNA damage.

Journal Title

Nucleic Acids Research

Volume

40

Issue/Number

19

Publication Date

1-1-2012

Document Type

Article

Language

English

First Page

9621

Last Page

9632

WOS Identifier

WOS:000310377200030

ISSN

0305-1048

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