Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing.
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.
Pirngruber
Judith
J
Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany.
Shchebet
Andrei
A
Johnsen
Steven A
SA
D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D006657:Histones / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D011494:Protein Kinases / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013045:Species Specificity
C118305:CTDK-I protein complex, S cerevisiae; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; C414163:SGV1 protein, S cerevisiae; D012319:RNA Polymerase II