CDK9 directs H2B monoubiquitination and controls replication‐dependent histone mRNA 3′‐end processing

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Abstract
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.