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Molecular and Cellular Biology, March 2007, p. 2059-2073, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01828-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Myc Transactivation Domain Promotes Global Phosphorylation of the RNA Polymerase II Carboxy-Terminal Domain Independently of Direct DNA Binding{triangledown} ,{dagger}

Victoria H. Cowling and Michael D. Cole*

Departments of Pharmacology and Genetics, Dartmouth Medical School, One Medical Center Drive, Lebanon, New Hampshire 03756

Received 26 September 2006/ Returned for modification 17 November 2006/ Accepted 5 January 2007

Myc is a transcription factor which is dependent on its DNA binding domain for transcriptional regulation of target genes. Here, we report the surprising finding that Myc mutants devoid of direct DNA binding activity and Myc target gene regulation can rescue a substantial fraction of the growth defect in myc–/– fibroblasts. Expression of the Myc transactivation domain alone induces a transcription-independent elevation of the RNA polymerase II (Pol II) C-terminal domain (CTD) kinases cyclin-dependent kinase 7 (CDK7) and CDK9 and a global increase in CTD phosphorylation. The Myc transactivation domain binds to the transcription initiation sites of these promoters and stimulates TFIIH binding in an MBII-dependent manner. Expression of the Myc transactivation domain increases CDK mRNA cap methylation, polysome loading, and the rate of translation. We find that some traditional Myc transcriptional target genes are also regulated by this Myc-driven translation mechanism. We propose that Myc transactivation domain-driven RNA Pol II CTD phosphorylation has broad effects on both transcription and mRNA metabolism.

* Corresponding author. Mailing address: Departments of Pharmacology and Genetics, Dartmouth Medical School, One Medical Center Drive, Lebanon, NH 03756. Phone: (603) 653-9975. Fax: (603) 653-9952. E-mail: mcole{at}dartmouth.edu.

{triangledown} Published ahead of print on 22 January 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, March 2007, p. 2059-2073, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.01828-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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