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Molecular and Cellular Biology, January 2005, p. 637-651, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.637-651.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Histone H2B Ubiquitylation Is Associated with Elongating RNA Polymerase II

Tiaojiang Xiao,1,{dagger} Cheng-Fu Kao,2,{dagger} Nevan J. Krogan,3 Zu-Wen Sun,4 Jack F. Greenblatt,3 Mary Ann Osley,2 and Brian D. Strahl1*

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina,1 Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico,2 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada,3 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee4

Received 20 September 2004/ Accepted 14 October 2004

Rad6-mediated ubiquitylation of histone H2B at lysine 123 has been linked to transcriptional activation and the regulation of lysine methylation on histone H3. However, how Rad6 and H2B ubiquitylation contribute to the transcription and histone methylation processes is poorly understood. Here, we show that the Paf1 transcription elongation complex and the E3 ligase for Rad6, Bre1, mediate an association of Rad6 with the hyperphosphorylated (elongating) form of RNA polymerase II (Pol II). This association appears to be necessary for the transcriptional activities of Rad6, as deletion of various Paf1 complex members or Bre1 abolishes H2B ubiquitylation (ubH2B) and reduces the recruitment of Rad6 to the promoters and transcribed regions of active genes. Using the inducible GAL1 gene as a model, we find that the recruitment of Rad6 upon activation occurs rapidly and transiently across the gene and coincides precisely with the appearance of Pol II. Significantly, during GAL1 activation in an rtf1 deletion mutant, Rad6 accumulates at the promoter but is absent from the transcribed region. This fact suggests that Rad6 is recruited to promoters independently of the Paf1 complex but then requires this complex for entrance into the coding region of genes in a Pol II-associated manner. In support of a role for Rad6-dependent H2B ubiquitylation in transcription elongation, we find that ubH2B levels are dramatically reduced in strains bearing mutations of the Pol II C-terminal domain (CTD) and abolished by inactivation of Kin28, the serine 5 CTD kinase that promotes the transition from initiation to elongation. Furthermore, synthetic genetic array analysis reveals that the Rad6 complex interacts genetically with a number of known or suspected transcription elongation factors. Finally, we show that Saccharomyces cerevisiae mutants bearing defects in the pathway to H2B ubiquitylation display transcription elongation defects as assayed by 6-azauracil sensitivity. Collectively, our results indicate a role for Rad6 and H2B ubiquitylation during the elongation cycle of transcription and suggest a mechanism by which H3 methylation may be regulated.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, 405 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7260. Phone: (919) 843-3896. Fax: (919) 966-2852. E-mail: brian_strahl{at}med.unc.edu.

{dagger} T.X. and C.-F.K. contributed equally to this work.

Molecular and Cellular Biology, January 2005, p. 637-651, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.637-651.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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