The Myc transactivation domain promotes global phosphorylation of the RNA polymerase II carboxy-terminal domain independently of direct DNA binding.
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.
Cowling
Victoria H
VH
Department of Pharmacology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Cole
Michael D
MD
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D048430:Cell Shape; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D051758:Transcription Factor TFIIH / Q000378:metabolism; D015533:Transcriptional Activation; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D016213:Cyclins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051758:Transcription Factor TFIIH; D004247:DNA; D042925:Positive Transcriptional Elongation Factor B; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D012319:RNA Polymerase II; D000095043:Cyclin-Dependent Kinase-Activating Kinase