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J. Biol. Chem., Vol. 283, Issue 15, 9555-9561, April 11, 2008

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Multiple Mechanisms Contribute to Inhibit Transcription in Response to DNA Damage^*

George F. Heine, Andrew A. Horwitz¹, and Jeffrey D. Parvin²

From the Department of Biomedical Informatics and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210 and the Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115

Cellular DNA damage elicits the phosphorylation and ubiquitination of RNA polymerase II (RNAPII), leading to the global repression of transcription. In this report we show that there are at least two different pathways to transcriptional repression, depending on the type of DNA damage. After H₂O₂ treatment, transcription was rapidly inhibited and rapidly restored. On the other hand, UV irradiation caused a much slower transcriptional inhibition, with a corresponding depletion of unphosphorylated RNAPII. We found that after UV treatment, but not treatment with H₂O₂, the inhibition of transcription was dependent on both the proteasome and new protein synthesis. In addition, RNAPII activity and ubiquitination were regulated through the phosphorylation of RNAPII by the P-TEFb kinase. These results highlight that multiple cellular pathways exist to globally repress transcriptional processes that might interfere with the repair of DNA damage.

Received for publication, September 13, 2007 , and in revised form, February 12, 2008.

^* This work was supported by National Institutes of Health NCI Postdoctoral Fellowship CA130302 (to G. F. H.), a predoctoral fellowship from the Department of Defense Breast Cancer Research Program (to A. A. H.), and National Institutes of Health Grant CA90281 (to J. D. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Dept. of Cellular and Molecular Pharmacology, University of California, 600 16th St., San Francisco, CA 94158-2517.

² To whom correspondence should be addressed: 960 Biomedical Research Tower, 460 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-0523; E-mail: Jeffrey.Parvin{at}OSUMC.edu.

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