Progression through the RNA polymerase II CTD cycle

Abstract

The C-terminal domain of RNA polymerase II's largest subunit undergoes dynamic phosphorylation during transcription, and the different phosphorylation patterns that predominate at each stage of transcription recruit the appropriate set of mRNA-processing and histone-modifying factors. Recent papers help to explain how the changes in CTD phosphorylation pattern are linked to the progression from initiation through elongation to termination.

Figure 1

Different stages in the RNA polymerase II CTD cycle. Physical or functional interactions are shown as black arrows, enzymatic activities with red arrows. Phosphorylations are shown as small pink (low level) or large red (high level) crosses. A. In the preinitiation complex (PIC), transcription activators (ACT) recruit RNApII by interacting with the Mediator (MED). Once in the PIC, Mediator stimulates the TFIIH kinase (H), which phosphorylates CTD Ser5 and Ser7. CTD phosphorylation then triggers Mediator dissociation. B. In early elongation, CTD Ser5P helps recruit mRNA capping enzymes, the H3K4 methyltransferase, and the yeast early termination pathway machinery. Ser7P (or 5P/7P) also recruits Integrator to mammalian snRNA genes. Early CTD Ser2 phosphorylation is triggered by association of the Cdk9/Bur1 kinase with Ser5P and/or capping enzymes. This kinase also phosphorylates the Spt4/5 elongation factor, which then contributes to elongation and nucleosome methylation via the PAF complex. Spt4/5 may also interact with mRNA capping enzymes (not shown). C. In late elongation, the yeast Ctk1/Lsk1 or mammalian Cdk9 kinases more extensively phosphorylate Ser2. This modification helps recruit Spt6 and the H3K36 methyltransferase to co-transcriptionally modify chromatin. Ser2P also interacts with polyadenylation and termination machinery at mRNA 3′ ends.