The Paf1 complex: platform or player in RNA polymerase II transcription?

Abstract

The Paf1 complex (Paf1C), composed of the proteins Paf1, Ctr9, Cdc73, Rtf1, and Leo1, accompanies RNA polymerase II (pol II) from the promoter to the 3' end formation site of mRNA and snoRNA encoding genes; it is also found associated with RNA polymerase I (pol I) on rDNA. The Paf1C is found in simple and complex eukaryotes; in human cells hSki8 is also part of the complex. The Paf1C has been linked to a large and growing list of transcription related processes including: communication with transcriptional activators; recruitment and activation of histone modification factors; facilitation of elongation on chromatin templates; and the recruitment of 3' end-processing factors necessary for accurate termination of transcription. Absence of, or mutations in, Paf1C factors result in alterations in gene expression that can result in misregulation of developmental programs and loss of control of cell division leading to cancer in humans. This review considers recent information that may help to resolve whether the Paf1C is primarily a "platform" on pol II that coordinates the association of many critical transcription factors, or if the complex itself plays a more direct role in one or more steps in transcription.

Figure 1. Overview of Paf1C Interactions with Transcriptional Activation, Histone Modification, Elongation and 3' End Formation Factors

Details of the various interactions depicted are described in the text.

Figure 2. Dynamic Association of the Paf1C with Pol II During Transcription

A. As described in the text the recruitment of the Paf1C minimally requires pol II and phosphorylation of Spt5 by the Bur1/2 cyclin/kinase. Many other factors are present on pol II during elongation including Bre1/Rad6 and the cleavage and poly(A) factor complexes CPF and CF1A. Increasing pol II CTD Ser2-P catalyzed by Ctk1 and Bur1 also helps to recruit histone modification and 3' end formation factors including Set2. Another transition occurs at the poly(A) site leading to release of the Paf1C and the kinases Bur1 and Ctk1 from pol II but retention of Spt4/5. B. As described in the text a loop including a subset of initiation and 3' end formation factors forms between the promoter and poly(A) sites in yeast. The differential localization of histone H3 modifications is described in the text. The Paf1C is present throughout the region defined as the elongation loop but is absent up- and downstream where the general initiation factors, mediator complex and termination factors respectively are present.

Figure 3. Histone H3 Trimethylation is Dependent on the Paf1C

Recruitment of the Paf1C to pol II requires the Bur1 kinase and the presence of Spt4/5 [63, 67, 69]. The Paf1C is not required for the initial recruitment of Rad6/Bre1[79] or known to be required for recruitment of Ctk1 [22], but it is required for the presence of the product of the two activities, H2BK123 ubiquitylation and CTD-Ser2 phosphorylation respectively. This could be due to a reduction in activity of the modifying enzymes in the absence of the Paf1C (without the Paf1C, Rad6/Bre1 does not spread into the coding region [79]), or to a stimulation of the modification removal activities (Ubp8 and Fcp1 as shown). Without modification of H2BK123 and the Ser2 of the pol II CTD there is no trimethylation of H3K4 by Set1 [78, 85] or H3K36 by Set2 [82, 83].

Figure 4. A Summary of Known Physical Interactions Within the Paf1C and Between the Paf1C and Other Factors

Interactions from a global two-hybrid screen shown as circles with thin black lines: Paf1/Leo1, Rtf1/Swc7, Ctr9/ Pex14-Pho81-Lap4-Dal80 [109]. All other interactions shown with thick gray borders: yeast factor interactions- Cdc73/pol II [6]; Rtf1/Chd1-Paf1-Ctr9 [86, 107]; Rtf1/Spt4/5-Spt16 [10, 11]; Cdc73/CPF-CF1A [22]; human factor interactions-hPaf1/hBre1-hDst1-hLeo1-hCtr9-hRtf1-hCdc73, hCdc73/hRtf1-hCtr9, and hCtr9/hSki8 [20, 106]; hCdc73/CPSF-CstF [24]; fly factor interactions- dCdc73/β-catenin [26], dCdc73/Gli [27]. A comprehensive listing of genetic and physical interactions can be found in the Saccharomyces Genome Database (http://www.yeastgenome.org).