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RNA polymerase II C-terminal domain: Tethering transcription to transcript and template.

The RNA polymerase II (Pol II) C-terminal domain (CTD) is a repetitive disordered domain that extends from the catalytic core of the enzyme. This “tail” domain is heavily modified by phosphorylation, glycosylation and proline isomerization. In addition to the enzymes that modify the tail a number of RNA processing factors and chromatin modification factors interact with the CTD. Thus, this domain acts as a tether to bring into close proximity the machinery necessary to synthesize and process Pol II transcripts. 
 
By definition the CTD consists of the amino acid sequences extending from the largest subunit, RPO21 or RPB1 in yeast and POLR2A in human. Specifically the CTD consists of sequences beyond the most C-terminal region that is conserved among the largest subunits of all multi-subunit RNA polymerases 1. This “H” homology region plays a role in positioning the catalytic core and provides surfaces for interactions with Rpb2 and Rpb6 2. The CTD thus consists of three regions (Figure 1). In order of proximity to the catalytic core these are the linker, the heptad repeats, and a C-terminal non-repeat or “tip” domain. The linker region is not conserved among different organisms but does contain an enrichment of amino acids found in the CTD. 
 
 
 
Figure 1 
 
Diagram showing the three regions of the CTD. 
 
 
 
The heptad repeat domain consists of multiple tandem repeats of the consensus sequence YSPTSPS. Since this sequences is tandemly repeated the consensus could be any one of seven permutations of this sequence. The selection of Tyr as position one is essentially arbitrary and other permutations have been proposed 1. Because the Tyr in position one is more universally adopted in the literature we will use this nomenclature in this review. 
 
The discovery of the CTD in the mid-1980’s 3 explained the multiple forms of Pol II that were identified by ion exchange chromatography4,5. These forms, termed Pol IIO, IIA and IIB differed by the mobility in SDS gels of the largest subunit termed IIo, IIa and IIb, respectively (Figure 2). Comparing the amino acid content of these different forms to the coding sequence revealed that the most rapidly migrating form, IIb, is a proteolytic breakdown product lacking the CTD 3a. Forms IIo and IIa both contain the CTD but differ in that IIo is highly phosphorylated as could be shown by labeling with 32P or by conversion of IIo to IIa by phosphatase treatment 6. The ability to separate phosphorylated and unphosphorylated CTD species by SDS gel electrophoresis has allowed the characterization of CTD phosphorylation states established both in vitro and in vivo. 
 
 
 
Figure 2 
 
Idealized SDS PAGE separation of the Rpb1 subunit. Increasing phosphatase treatment increases the mobility of the IIo form while proteolysis increases the mobility of both forms. x refers to intermediate phosphorylation states while y refers to intermediates ... 
 
 
 
The existence of both the IIO and IIA forms of Pol II in vivo led to the discovery that Pol II undergoes reversible phosphorylation with the unphosphorylated IIA form functioning in initiation and the phosphorylated IIO form carrying out the elongation step 7. Genetic and biochemical studies showed that multiple sites in the CTD heptad repeats could be phosphorylated and these sites were not functionally equivalent 8. Mapping different CTD phosphorylations to different chromatin sites in coding regions led to the “CTD code” hypothesis in which different phosphorylation states exist in the initiation, elongation and termination phases of the transcription cycle for the purpose of recruiting the appropriate factors to carry out the needed processing reactions 9. 
 
In this review we will focus on the general properties of the CTD and its modification and interactions with CTD-binding proteins. Gene-specific aspects of CTD function will be discussed in accompanying reviews by Jeronimo et al. and Eick and Geyer. To set the stage for discussing the CTD we will consider the evolution of this domain. We will then discuss structural studies of the CTD. Genetic and gene expression effects of altering the CTD will then be considered. Finally, we will discuss the kinases phosphatases and proline isomerases that establish the code and the CTD-binding proteins that read the code.