Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 7, Pages 5012-5022Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.176628
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Funding
- Canadian Institutes for Health Research, Genome Canada, Genome Quebec
- Natural Sciences and Engineering Research Council of Canada
- Canadian Foundation for Innovation
- Canadian Institutes of Health Research
- Fonds de Recherche en Sante du Quebec
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Elongation of transcription by mammalian RNA polymerase II (RNAPII) is regulated by specific factors, including transcription factor IIS (TFIIS) and positive transcription elongation factor b (P-TEFb). We show that the E3 ubiquitin ligase UBR5 associates with the CDK9 subunit of positive transcription elongation factor b to mediate its polyubiquitination in human cells. TFIIS also binds UBR5 to stimulate CDK9 polyubiquitination. Co-localization of UBR5, CDK9, and TFIIS along specific regions of the gamma fibrinogen (gamma FBG) gene indicates that a ternary complex involving these factors participates in the transcriptional regulation of this gene. In support of this notion, overexpression of TFIIS not only modifies the ubiquitination pattern of CDK9 in vivo but also increases the association of CDK9 with various regions of the gamma FBG gene. Notably, the TFIIS-mediated increase in CDK9 loading is obtained during both basal and activated transcription of the gamma FBG gene. This increased CDK9 binding is paralleled by an increase in the recruitment of RNAPII along the gamma FBG gene and the phosphorylation of the C-terminal domain of the RNAPII largest subunit RPB1 on Ser-2, a known target of CDK9. Together, these results identify UBR5 as a novel E3 ligase that regulates transcription and define an additional function of TFIIS in the regulation of CDK9.
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