Modifications of RNA polymerase II CTD: Connections to the histone code and cellular function

PHF13: A new player involved in RNA polymerase II transcriptional regulation and co-transcriptional splicing

“…3 The CTD of RNAPII can be phosphorylated at Y 1 , S 2 , T 4 , S 5 and S 7 and the phosphorylation of each of these residues is affiliated with distinct functions in the transcription cycle. 4 All of these residues are important for cell viability and their substitution to either phenylalanine or alanine, nonphosphorylatable residues, is lethal. 3,4 Similarly mutation of S 2 , T 4 , S 5 or S 7 with glutamate, an acidic phospho-mimic is lethal, 5,6 indicating that RNAPII's ability to return to a hypo-phosphorylated state is as important as the sequential phosphorylation of its CTD.…”

“…4 All of these residues are important for cell viability and their substitution to either phenylalanine or alanine, nonphosphorylatable residues, is lethal. 3,4 Similarly mutation of S 2 , T 4 , S 5 or S 7 with glutamate, an acidic phospho-mimic is lethal, 5,6 indicating that RNAPII's ability to return to a hypo-phosphorylated state is as important as the sequential phosphorylation of its CTD. Hypo-phosphorylated RNAPII is recruited to promoters with the help of the general transcription factors (TFIIA-TFIIH) and mediator complex which assemble to form the pre-initiation complex (PIC).…”

“…7 The PIC is phosphorylated by Cdk7, a component of the general transcription factor TFIIH, at position S5 and S7 of RNAPII CTD, causing its release from the mediator complex and leading to its translocation to the TSS or just downstream of the TSS. 4,8,9 RNAPII S5P/S7P is transcriptionally competent but is paused before elongation, a delay that is stabilized by the recruitment of two negative regulators of transcription, namely negative elongation factor (NELF) and DRB sensitivity inducing factor (DSIF). 10 In order for productive transcriptional elongation to commence, Cdk9 phosphorylates both NELF and DSIF converting them into positive regulators of transcription and concomitantly phosphorylates S2.…”

“…11,12 Early in transcription elongating RNAPII is phosphorylated at S2 and S5, and as elongation proceeds S5P is successively removed whereas S2P gradually increases toward the 3 0 end. 4 Therefore, the phosphorylation status of the CTD domain and key regulatory interacting factors is mediated by specific Cdk kinases, which in turn regulates the transcription cycle. Interestingly, PHF13 also contains several putative SP/TP Cdk phosphorylation sites and a Cdk consensus sequence S/T RX K/ R, 13 raising the possibility that it may also be a substrate of Cdk7 and/or Cdk9.…”

“…4,8,[14][15][16] Thus, RNAPII S5P localizes to different chromatin regions, including repressed bivalent genes, 14 active promoters/promoter proximal regions 3 and at splice site junctions. 3,15 Furthermore, most of these RNAPII S5P contexts are affiliated with a pausing of RNAPII, 14,17,18 indicating that S5P is additionally important for co-transcriptional processing of pre-mRNA.…”