Review
Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

https://doi.org/10.1016/j.tibs.2017.08.003Get rights and content

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Paf1C can be recruited to genes by transcriptional activators and through interactions with the Pol II elongation machinery.

Paf1C can function to maintain promoter-proximal pausing of Pol II or to promote release from pausing, depending upon the genetic context.

Paf1C regulates cleavage and polyadenylation of mRNA, governs polyA site selection, and controls the export of nascent transcripts.

Paf1C controls chromatin structure by promoting several cotranscriptional histone modifications and is important for the establishment of proper boundaries between heterochromatin and euchromatin.

Paf1C regulates pluripotency and development in higher eukaryotes, and several new studies link Paf1C misregulation to cancer.

The conserved, multifunctional Polymerase-Associated Factor 1 complex (Paf1C) regulates all stages of the RNA polymerase (Pol) II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that various functions of Paf1C, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase.

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.

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