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. 2012:2012:347214.
doi: 10.1155/2012/347214. Epub 2012 Feb 26.

Emerging Views on the CTD Code

David W Zhang  1 , Juan B Rodríguez-Molina, Joshua R Tietjen, Corey M Nemec, Aseem Z Ansari
Affiliations

Emerging Views on the CTD Code

David W Zhang et al. Genet Res Int. 2012.

Abstract

The C-terminal domain (CTD) of RNA polymerase II (Pol II) consists of conserved heptapeptide repeats that function as a binding platform for different protein complexes involved in transcription, RNA processing, export, and chromatin remodeling. The CTD repeats are subject to sequential waves of posttranslational modifications during specific stages of the transcription cycle. These patterned modifications have led to the postulation of the "CTD code" hypothesis, where stage-specific patterns define a spatiotemporal code that is recognized by the appropriate interacting partners. Here, we highlight the role of CTD modifications in directing transcription initiation, elongation, and termination. We examine the major readers, writers, and erasers of the CTD code and examine the relevance of describing patterns of posttranslational modifications as a "code." Finally, we discuss major questions regarding the function of the newly discovered CTD modifications and the fundamental insights into transcription regulation that will necessarily emerge upon addressing those challenges.

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Figures

Figure 1
Figure 1
RNA polymerase II structure. (a) Side view of the core Pol II crystal structure containing all twelve subunits and displaying the RNA exit channel (bold arrow) and the positioning of the CTD adapted from Armache et al. [71]. Cartoon in the upper right displays the color coding for the Pol II subunits used in the crystal structure. (b) Illustration of the relative length(s) between the CTD in various conformations and the core Pol II adapted from Meinhart et al. [72]. RNA positioning (red) upon exit of the Pol II and the positioning of the DNA template (blue) upstream and downstream of the core Pol II are also displayed. (c) Known modifications possible on the Pol II CTD are displayed. Glycosylation and phosphorylation are mutually exclusive modifications. Structural images of a heptad repeat in the cis- and trans-conformation are also shown [–75]. G: β-O-linked N-acetylglucosamine [76]; P: O-linked phosphate.
Figure 2
Figure 2
The primary components of the RNA biogenesis machinery and their interactions with the RNA polymerase II C-terminal domain (CTD). Briefly, hypophosphorylated Pol II assembles at the preinitiation complex (PIC) with the Mediator and general transcription factors (GTFs), with TFIIH associating last. The TFIIH-associated kinase Kin28 phosphorylates Ser5 (shown in red) and Ser7 (shown in purple) on the CTD. Mediator-associated kinase Srb10 also contributes to the phosphorylation of Ser5-P. This mark enables promoter release and mediates interactions with the capping enzyme (CE) complex, Nrd1 component of termination machinery, and Set1 histone methyltransferase, which places trimethyl marks on histone H3K4. The Ser5-P mark also facilitates recruitment of Bur1 kinase. Bur1 places initial Ser2-P marks, which facilitate recruitment of Ctk1 kinase, and continues to replenish Ser7-P marks during elongation. Ctk1 is the primary Ser2 kinase, and its phosphorylation recruits splicing machinery (SP) through Prp40, as well as Set2 histone methyltransferase, which places di- and trimethyl marks on histone H3K36. Cleavage and polyadenylation (PA) machinery are recruited through many factors associating with the CTD. One of the factors, Pcf11, binds cooperatively to Ser2-P with Rtt103. The exonuclease complex (Exo) is also recruited through interaction between CTD and Rtt103 and through cooperative interaction between Rtt103 and Pcf11. Finally, the hypophosphorylated CTD is regenerated through three CTD phosphatases. Ser2-P is removed by the phosphatase Fcp1, while two phosphatases, Rtr1 and Ssu72, combine to remove Ser5-P marks during elongation and at termination, respectively. Upon de-phosphorylation, Pol II is released with the assistance of a mechanism involving Pcf11 and can begin another cycle of transcription.
Figure 3
Figure 3
Recruitment and composition of PIC components. Sequential recruitment of the Mediator complex, GTFs, and Pol II (left) or the recruitment of the Pol II holoenzyme (top right), which assembles the pre-initiation complex (PIC) at promoters (bottom right).
Figure 4
Figure 4
Bur1 phosphorylation of the CTD facilitates the transition from initiation to elongation. (a) Ser5-P enhances recruitment and subsequent phosphorylation of Ser2 by Bur1. Bur1 also phosphorylates Spt5, which acts with the Paf1 complex to promote elongation. (b) CTD phosphorylation by Bur1 enhances the activity of Ctk1 on Ser2. The majority of the Ser2-P is maintained by competition between phosphorylation by Ctk1 and dephosphorylation by Fcp1. This increase in Ser2-P facilitates recruitment of many Ser2-P-binding proteins, such as Npl3.
Figure 5
Figure 5
Nrd1-dependent termination pathway. The Nrd1-Nab3-Sen1 complex is recruited via interaction between Nrd1 and Ser5-P. This recruitment is facilitated by H3K4me3, which is placed by the Set1 histone methyltransferase. The mechanisms by which the Ssu72 and Glc7 phosphatases promote termination are still unclear, but it may be that the dephosphorylation of Sen1 by Glc7 and of the CTD by Ssu72 causes the polymerase to pause, and allowing the termination machinery to associate. During elongation, both Nrd1 and Nab3 scan the nascent RNA for their preferred sequences (see text for details). Upon finding their concensus sequences, Nrd1-Nab3-Sen1 complex is able to be associated with the RNA. The endonucleases Rnt1 and Ysh1 may contribute to the cleavage of the RNA, which is followed by 3′-5′ trimming the transcript by the TRAMP complex and by the degradation of the remaining RNA exiting Pol II by the 5′-3′ exonuclease Rat1 (Exo).
Figure 6
Figure 6
The mRNA termination pathway. Rna15 competes with Npl3 for binding to the nascent RNA. CK2 phosphorylates Npl3, allowing Rna15 to find its preferred binding site (an A/U-rich region) in the RNA. The CPF and CFIA components assemble through interactions with the CTD and the Yth1 component of CPF cleaves the nascent RNA at the polyadenylation site, followed by polyadenylation by Pap1. Then the Rat1 exonuclease complex associates via cooperative interaction between Pcf11 and Rtt103 and leads to termination and dissociation of Pol II.
Figure 7
Figure 7
Sus1 in TREX2 and SAGA complexes coordinates mRNA export. (a) Subunit compositions of TREX2 and SAGA complexes are shown, highlighting Sus1 (asterisk). (b) mRNA export coordinated by Sus1. Sus1 binds Ser2-P and Ser2-P/Ser5-P CTD, connecting the CTD to the SAGA histone acetyltransferase complex. Sus1 also interacts with Yra1 component of the THO/TREX complex on the RNA. Mex67-Mtr2 are recruited by interaction with Yra1 and help form the export-competent mRNP. At the nuclear pore complex (NPC), Mlp1-Mlp2 interact with the polyA mRNA-binding protein Nab2 and Mex67 interacts with Sac3 of the TREX2 complex. This interaction brings the export-competent mRNP to the NPC in preparation for export to the cytoplasm. Sus1 is a component of both TREX2 and SAGA and serves to tether actively transcribed gene promoters to the NPC.
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