CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing.
Post-translational histone modifications have essential roles in controlling nuclear processes; however, the specific mechanisms regulating these modifications and their combinatorial activities remain elusive. Cyclin-dependent kinase 9 (CDK9) regulates gene expression by phosphorylating transcriptional regulatory proteins, including the RNA polymerase II carboxy-terminal domain. Here, we show that CDK9 activity is essential for maintaining global and gene-associated levels of histone H2B monoubiquitination (H2Bub1). Furthermore, CDK9 activity and H2Bub1 help to maintain correct replication-dependent histone messenger RNA (mRNA) 3'-end processing. CDK9 knockdown consistently resulted in inefficient recognition of the correct mRNA 3'-end cleavage site and led to increased read-through of RNA polymerase II to an alternative downstream polyadenylation signal. Thus, CDK9 acts to integrate phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing.
Pirngruber
Judith
J
Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany.
Shchebet
Andrei
A
Schreiber
Lisa
L
Shema
Efrat
E
Minsky
Neri
N
Chapman
Rob D
RD
Eick
Dirk
D
Aylon
Yael
Y
Oren
Moshe
M
Johnsen
Steven A
SA
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D003609:Dactinomycin / Q000494:pharmacology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology; D054875:Ubiquitination / Q000235:genetics
D005419:Flavonoids; D006657:Histones; D019384:Nucleic Acid Synthesis Inhibitors; D010880:Piperidines; D012333:RNA, Messenger; D003609:Dactinomycin; C077990:alvocidib; D004004:Dichlororibofuranosylbenzimidazole; C506646:RNF20 protein, human; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases; D042863:Cyclin-Dependent Kinase 9