Trends in Biochemical Sciences
ReviewEmerging Insights into the Roles of the Paf1 Complex in Gene Regulation
Section snippets
The Multifunctional Paf1 Complex
Each stage of the Pol II transcription cycle is extensively regulated by accessory proteins that directly impact Pol II activity, mediate its response to additional regulatory proteins or modify the chromatin template. The focus of this review, Paf1C, has been implicated in regulating all stages of the Pol II transcription cycle as well as events that follow transcript synthesis. Since the discovery of Paf1C as a novel Pol II-interacting complex in Saccharomyces cerevisiae over 20 years ago 1, 2
Mechanisms of Targeting Paf1C to Chromatin
In budding yeast, Paf1C is composed of five subunits: Paf1, Ctr9, Cdc73, Leo1, and Rtf1. Some organisms, including humans, contain an additional subunit, the multifunctional Ski8/Wdr61 protein [29]. Moreover, in organisms other than budding yeast, ranging from fission yeast to humans, Rtf1 is not strongly associated with Paf1C and has been shown to function independently of other Paf1C subunits in certain contexts 18, 30, 31. Although none of the subunits is essential in budding yeast, cells
Paf1C Regulates Gene Expression through Diverse Mechanisms
Strong support for a role of Paf1C in transcription elongation first came from experiments in budding yeast, which showed that Paf1C is recruited to actively transcribed open reading frames (ORFs) [52] and interacts physically and genetically with transcription elongation factors, including the Spt4–Spt5 complex and the FACT histone chaperone complex 4, 5, 53. An early study using yeast extracts and a naked DNA template revealed a direct role for Paf1C as a positive effector of transcription in
Paf1C Governs Chromatin Structure
Eukaryotic transcription takes place on chromatin, and post-translational modification of the core histone proteins regulates Pol II transcription by effecting dynamic changes in chromatin. Paf1C was first implicated in the regulation of cotranscriptional histone modifications by studies showing that it is required for the conserved monoubiquitylation (ub) of a lysine near the C terminus of histone H2B (K123 in budding yeast, and K120 in humans), as well as H2Bub-dependent methylation of H3 K4
Paf1C Connections to Development and Human Disease
In spite of the diverse and context-dependent functions of Paf1C, its role as a regulator of Pol II transcription is broadly conserved across eukaryotes, and interest in Paf1C has continued to grow as its role in development and human disease has become more evident. Historically, interest was focused on the parafibromin (Cdc73) subunit, a tumor suppressor that, when mutated, can lead to hyperparathyroidism/jaw tumor syndrome [83]. More recently, CTR9 was also identified as a tumor suppressor
Concluding Remarks
Since its discovery in budding yeast, the functions attributed to the conserved Paf1C have expanded dramatically as has interest in the ways it regulates gene expression in higher eukaryotes. Moving forward, it will be especially important to identify the detailed mechanisms that control Pol II pausing in metazoans and to clarify why Paf1C imposes pausing in some settings while preventing it in others (see Outstanding Questions). It will also be important to elucidate the mechanisms, interplay,
Acknowledgments
We thank members of the Arndt Laboratory for their valuable advice and critical reading of the manuscript. This work was supported by NIH grant GM052593.
References (92)
A novel collection of accessory factors associated with yeast RNA polymerase II
Protein Expr. Purif.
(1996)The Paf1 complex has functions independent of actively transcribing RNA polymerase II
Mol. Cell
(2004)A posttranscriptional role for the yeast Paf1–RNA polymerase II complex is revealed by identification of primary targets
Mol. Cell
(2005)The Rtf1 component of the Paf1 transcriptional elongation complex is required for ubiquitination of histone H2B
J. Biol. Chem.
(2003)The Paf1 complex is essential for histone monoubiquitination by the Rad6–Bre1 complex, which signals for histone methylation by COMPASS and Dot1p
J. Biol. Chem.
(2003)Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity
Mol. Cell
(2003)The Paf1 complex is required for histone H3 methylation by COMPASS and Dot1p: linking transcriptional elongation to histone methylation
Mol. Cell
(2003)PAF1, a molecular regulator of promoter-proximal pausing by RNA polymerase II
Cell
(2015)The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 and is involved in crosstalk with H3 K4 and K79 methylation
Mol. Cell
(2011)Human RNA polymerase II associated factor 1 complex promotes tumorigenesis by activating c-MYC transcription in non-small cell lung cancer
Biochem. Biophys. Res. Commun.
(2015)