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Although much has been learned about CDK12 and its activity, due to the lack of a specific inhibitor and the complications posed by long term RNAi depletion, much is still unknown about the particulars of CDK12 function. The coupling of transcription and associated processes has been shown to be dependent on the RNA polymerase II (RNAPII) C-terminal repeat domain (CTD) and the phosphorylation of the heptad repeats of which it is composed (consensus sequence Y1S2P3T4S5P6S7). The human transcription elongation regulator TCERG1 physically couples transcription elongation and splicing events by interacting with splicing factors through its N-terminal WW domains and the hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II through its C-terminal FF domains. “Specific interaction of the TCERG1 FF4-6 tandem repeat domains with RNA polymerase II requires simultaneous phosphorylation at Ser2, Ser5 and Ser7 of the CTD.” Faseb Journal, vol. RNA polymerase II translocates across much of the genome and since it can be blocked by many kinds of DNA lesions, detects DNA damage proficiently; it thereby contributes to DNA repair and to normal levels of DNA damage resistance.Therefore gaining a better understanding of CDK12's roles at the molecular level will be challenging without the development of additional tools. Two primary S2 position CTD kinases have been identified in higher eukaryotes: P-TEFb and CDK12/Cyclin K. Here, we report biochemical and structural characterization of the C-terminal three FF domains (FF4-6) of TCERG1, revealing a rigid integral domain structure of the tandem FF repeat that interacts with the hyperphosphorylated CTD (PCTD). However, the components and mechanisms that respond to polymerase blockage are largely unknown, except in the case of UV-induced damage that is corrected by nucleotide excision repair.In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes.Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death.Fewer studies on CKD13 have clearly shown that it is functionally distinct from CDK12.CDK13 is important for proper expression of a number of genes, but it also probably plays yet-to-be-discovered roles in other processes.
The proteomic content of native complexes in total and size-fractionated extracts was determined using highly sensitive LC-MS/MS.
To gain a thorough understanding of relevant phosphorylation events on the PCTD, we identified the principal elongation-phase CTD kinase activities in three different eukaryotes, yeast (y Ctk1), Drosophila (d CDK12) and humans (h CDK12 & 13).
In addition, we described a novel set of phospho CTD-associating proteins (“PCAPs”) that we now are investigating primarily in human cells.
By the end of the first decade both proteins had been qualified as CTD kinases, and it was emerging that both are heterodimers containing a Cyclin K subunit.
Since then, many studies on CDK12 have shown that, through phosphorylating the CTD of transcribing RNAPII, it plays critical roles in several stages of gene expression, notably RNA processing; it is also crucial for maintaining genome stability.