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J. Biol. Chem., Vol. 279, Issue 24, 24957-24964, June 11, 2004

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C-terminal Repeat Domain Kinase I Phosphorylates Ser2 and Ser5 of RNA Polymerase II C-terminal Domain Repeats^*

Janice C. Jones, Hemali P. Phatnani, Timothy A. Haystead, Justin A. MacDonald, S. Munir Alam¶, and Arno L. Greenleaf||

From the Department of Biochemistry, the Department of Pharmacology and Cancer Biology, and the ^¶Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 27710

The C-terminal repeat domain (CTD) of the largest subunit of RNA polymerase II is composed of tandem heptad repeats with consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. In yeast, this heptad sequence is repeated about 26 times, and it becomes hyperphosphorylated during transcription predominantly at serines 2 and 5. A network of kinases and phosphatases combine to determine the CTD phosphorylation pattern. We sought to determine the positional specificity of phosphorylation by yeast CTD kinase-I (CTDK-I), an enzyme implicated in various nuclear processes including elongation and pre-mRNA 3'-end formation. Toward this end, we characterized monoclonal antibodies commonly employed to study CTD phosphorylation patterns and found that the H5 monoclonal antibody reacts with CTD species phosphorylated at Ser2 and/or Ser5. We therefore used antibody-independent methods to study CTDK-I, and we found that CTDK-I phosphorylates Ser5 of the CTD if the CTD substrate is either unphosphorylated or prephosphorylated at Ser2. When Ser5 is already phosphorylated, CTDK-I phosphorylates Ser2 of the CTD. We also observed that CTDK-I efficiently generates doubly phosphorylated CTD repeats; CTD substrates that already contain Ser2-PO₄ or Ser5-PO₄ are more readily phosphorylated CTDK-I than unphosphorylby ated CTD substrates.

Received for publication, February 27, 2004 , and in revised form, March 24, 2004.

^* This work was supported by National Institutes of Health Grant GM40505 (to A. L. G.). 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.

^|| To whom correspondence should be addressed. Tel.: 919-684-4030; Fax: 919-684-8885; E-mail: arno{at}biochem.duke.edu.

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