Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing

Abstract

Cyclin-dependent kinase-9 (CDK9) was originally characterized as a transcription elongation factor which regulates RNA Polymerase II (RNAPII) activity following transcriptional initiation. However, recent evidence from a number of studies have shown that CDK9 plays an important role in regulating not only RNAPII activity but also co-transcriptional histone modification and mRNA processing events such as splicing and 3' end processing. Importantly, our previous work and the work presented here demonstrate that CDK9 functions to guide a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3. This function appears to be dependent upon not only the phosphorylation of the RNA Polymerase II C-terminal domain but also upon other CDK9 targets such as the Suppressor of Ty Homolog-5 (SUPT5H), Negative Elongation Factor-E (NELF-E) and probably the human Rad6 homolog UBE2A. We provide a working model by which CDK9 may control co-transcriptional replication-dependent histone mRNA 3' end processing in an H2Bub1 and H3K4me3-dependent manner and uncover new and important differences between the functions of human CDK9 and its yeast counterparts Ctk1 and Bur1.