The RNA polymerase II CTD “orphan” residues: Emerging insights into the functions of Tyr-1, Thr-4, and Ser-7

Abstract

The C-terminal domain (CTD) of the RNA polymerase II largest subunit consists of a unique repeated heptad sequence of the consensus Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. An important function of the CTD is to couple transcription with RNA processing reactions that occur during the initiation, elongation, and termination phases of transcription. During this transcription cycle, the CTD is subject to extensive modification, primarily phosphorylation, on its non-proline residues. Reversible phosphorylation of Ser2 and Ser5 is well known to play important and general functions during transcription in all eukaryotes. More recent studies have enhanced our understanding of Tyr1, Thr4, and Ser7, and what have been previously characterized as unknown or specialized functions for these residues has changed to a more fine-detailed map of transcriptional regulation that highlights similarities as well as significant differences between organisms. Here, we review recent findings on the function and modification of these three residues, which further illustrate the importance of the CTD in precisely modulating gene expression.

Tyr1 phosphorylation promotes phosphorylation of Ser2 on the C-terminal domain of eukaryotic RNA polymerase II by P-TEFb

“…Although substitution of non-tyrosine residues at the Tyr1 position is relatively rare in nature and does not occur in human cells, Tyr1 phosphorylation is conserved from yeast to humans and plays a key role in transcriptional events (Chapman et al, 2008; Yurko and Manley, 2018). Since the molecular mechanism explaining its diverse biological functions remains elusive, the sensitivity of CTD kinases to the chemical properties of Tyr1 side-chain motivated us to investigate if Tyr1 phosphorylation impacts subsequent phosphorylation events by reconstructing sequential CTD phosphorylation in vitro.…”

Crosstalk between RNA Pol II C-Terminal Domain Acetylation and Phosphorylation via RPRD Proteins

“…The heptad repeats within the CTD are extensively and dynamically post-translationally modified at different times during the transcription cycle. Of the seven consensus CTD residues, five can be phosphorylated (Y1, S2, T4, S5, and S7), and the two remaining proline residues can undergo isomerization to cis or trans conformations (Heidemann et al, 2013;Yurko and Manley, 2018). Serine-5 phosphorylation (S5p) and serine-2 phosphorylation (S2p) are the most thoroughly studied CTD modifications (Jasnovidova and Stefl, 2013;Buratowski, 2009;Harlen and Churchman, 2017).…”

Ssu72 Dual-Specific Protein Phosphatase: From Gene to Diseases

“…It has previously been reported that Pin1 can increase Ssu72′s phosphatase activity for Ser7P and Ser5P [ 44 ]. As mentioned above, the CTD of the largest subunit of RNAPII contains a unique repeated heptad sequence of the consensus Tyr1–Ser2–Pro3–Thr4–Ser5–Pro6–Ser7 [ 45 ]. This phosphorylation profile comprises an informational code coordinating transcription and RNA processing.…”