PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II

Chen, Fei Xavier; Woodfin, Ashley R.; Gardini, Alessandro; Rickels, Ryan; Marshall, Stacy A.; Smith, Edwin R.; Shiekhattar, Ramin; Shilatifard, Ali

doi:10.1016/j.cell.2015.07.042

Cited by 218 publications

(244 citation statements)

References 61 publications

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“…Consistent with these observations, the PAF1 complex has been shown to positively affect RNA polymerase II pause release and transcriptional elongation (42)(43)(44). Other studies have revealed an inhibitory effect of the PAF1 complex on elongation (45)(46)(47)(48). Thus, it has been proposed that the genetic background and physiological state of different cells may affect the output of the PAF1 complex (42).…”

supporting

confidence: 66%

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PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters

Gerlach

Furrer

Gallant

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The Myc oncogene is a transcription factor with a powerful grip on cellular growth and proliferation. The physical interaction of Myc with the E-box DNA motif has been extensively characterized, but it is less clear whether this sequence-specific interaction is sufficient for Myc's binding to its transcriptional targets. Here we identify the PAF1 complex, and specifically its component Leo1, as a factor that helps recruit Myc to target genes. Since the PAF1 complex is typically associated with active genes, this interaction with Leo1 contributes to Myc targeting to open promoters.

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supporting

confidence: 66%

“…targets were shown to be up-regulated by 10% on knockdown of Cdc73 (48), and efficient depletion of Paf1 altered the average expression of a group of 4,855 direct PAF1 targets by <10% (46). Nevertheless, the PAF1 complex is essential for the survival of metazoans.…”

Section: Significancementioning

confidence: 99%

PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters

Gerlach

Furrer

Gallant

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Release of the paused polymerase is achieved with P-TEFb phosphorylation of DSIF and NELF, ejecting NELF from pol II and converting DSIF into a positive elongation factor (14,15). The more recent discoveries of additional factors likely involved in pause establishment and release include human capping enzyme (16), the TFIIH-associated kinase, CDK7 (17,18), the TFIIH ERCC3 helicase (19), Mediator (20 -22), Integrator (23,24), ELL (25), TFIIS (26), TRIM28-KAP1-TIF1␤ (27,28), Top1 (29), SEC (30), PAF complex (31,32), and Gdown1 (33). The plethora of factors suggests that more complicated dynamics are at play in regulating pausing and elongation.…”

mentioning

confidence: 99%

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

Resto

Kim

Fernandez

et al. 2016

Journal of Biological Chemistry

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We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, whereas in a purified system devoid of OGA the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA polymerase II (pol II) pausing/elongation factors SPT5 and TRIM28-KAP1-TIF1␤, and a purified OGA-SPT5-TIF1␤ complex has elongation properties. Lastly, ChIP-seq experiments show that OGA maps to the transcriptional start site/5 ends of genes, showing considerable overlap with RNA pol II, SPT5, TRIM28-KAP1-TIF1␤, and O-GlcNAc itself. These data all point to OGA as a component of the RNA pol II elongation machinery regulating elongation genome-wide. Our results add a novel and unexpected dimension to the regulation of elongation by the insertion of O-GlcNAc cycling into the pol II elongation regulatory dynamics.RNA polymerase II is the species of polymerase that transcribes the protein-coding genes in the cell. Largely based on in vitro transcription data and bacterial transcriptional regulation, it was thought that the pathway of transcription initiation was the de novo assembly and recruitment of general factors and pol II 4 into a preinitiation complex at promoters. In other words, transcription was solely controlled by whether initiation occurred or not. However, in the late 1980s, a transcriptionally engaged pol II was found on several genes, located roughly at ϩ50 relative to the transcriptional start site (TSS) (1-3). More recently, genome-wide approaches have shown that paused pol II exists on at least 40% of promoters in the genome (4 -9).These data show that the regulation of elongation is a significant and widespread method by which cells regulate gene expression.Biochemically, the establishment of a paused polymerase requires the recruitment of DSIF and NELF to pol II early in elongation to prevent pol II from productive elongation (10 -13). Release of the paused polymerase is achieved with P-TEFb phosphorylation of DSIF and NELF, ejecting NELF from pol II and converting DSIF into a positive elongation factor (14,15). The more recent discoveries of additional factors likely involved in pause establishment and release include human capping enzyme (16), the TFIIH-associated kinase, CDK7 (17, 18), the TFIIH ERCC3 helicase (19), , Integrator (23,24), ELL (25), TFIIS (26), TRIM28-KAP1-TIF1␤ (27, 28), Top1 (29), SEC (30), PAF complex (31, 32), and Gdown1 (33). The plethora of factors suggests that more complicated dynamics are at play in regulating pausing and elongation. Additionally, it is not clear, and indeed difficult to know, whether all of the factors involved in pol II pausing and elongation have been identified. This difficulty is due mostly to the absence of a human cell-based in vitro transcription system that recapitulates a paused polymerase and with which the full complement of...

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“…ChIP-seq (ChIP combined with deep sequencing) analyses of all of the PAFc subunits will help clarify the dependence or independence of PAFc subunits in the context of the ERα regulatory network. As shown in a recent study (Chen et al 2015), a high-quality ChIP-grade antibody for Ctr9 is not yet available.…”

Section: Discussionmentioning

confidence: 99%

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Zeng

2015

Genes Dev.

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The human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases, including cancer. However, its involvement in breast cancer awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold subunit in hPAFc, is highly expressed in estrogen receptor α-positive (ERα + ) luminal breast cancer, and the high expression of Ctr9 correlates with poor prognosis. Knockdown of Ctr9 in ERα + breast cancer cells almost completely erased estrogen-regulated transcriptional response. At the molecular level, Ctr9 enhances ERα protein stability, promotes recruitment of ERα and RNAPII, and stimulates transcription elongation and transcription-coupled histone modifications. Knockdown of Ctr9, but not other hPAFc subunits, alters the morphology, proliferative capacity, and tamoxifen sensitivity of ERα + breast cancer cells. Together, our study reveals that Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERα + breast tumorigenesis, rendering it a potential target for the treatment of ERα + breast cancer.

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PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II

Cited by 218 publications

References 61 publications

PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters

PAF1 complex component Leo1 helps recruit Drosophila Myc to promoters

O-GlcNAcase Is an RNA Polymerase II Elongation Factor Coupled to Pausing Factors SPT5 and TIF1β

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

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