The Human PAF1 Complex Acts in Chromatin Transcription Elongation Both Independently and Cooperatively with SII/TFIIS

Kim, Jaehoon; Guermah, Mohamed; Roeder, Robert G.

doi:10.1016/j.cell.2009.12.050

Cited by 227 publications

(298 citation statements)

References 59 publications

(92 reference statements)

Supporting

Mentioning

274

Contrasting

Unclassified

Order By: Relevance

“…S3). Our findings are in agreement with previous reports that Ctr9 plays a pivotal role in PAF1c assembly (19), and further indicate that Leo1 might (C) Western blots showed the expression levels of CARM1 WT and CARM1 VLD were comparable to the endogenous CARM1 in MCF7 cells when endogenous CARM1 was efficiently silenced. (D and E) ChIP analyses showed that expression of the enzyme-defective CARM1 VLD mutant was insufficient to restore H3R17me2a level (D, *P < 0.01) and recruit PAF1c to pS2 ERE (E, *P < 0.01).…”

Section: Paf1c and Carm1 Coordinately Regulate A Common Set Of Erαsupporting

confidence: 83%

“…To establish the functional role of PAF1c in CARM1-regulated transcription, we attempted to knockdown PAF1c components and measure the effects on mRNA levels of CARM1-regulated ER targets. Knocking down Ctr9 was previously reported to affect expression of other PAF1c subunits in yeast and human cells (17,18), and Ctr9 and Paf1 were shown as scaffold proteins for the formation of PAF1c (19). Therefore, we generated a Dox-inducible Ctr9 knockdown cell line, MCF7-tet-on-shCtr9, which allows transient knockdown of Ctr9 to minimize cellular toxicity associated with the loss of functional PAF1c.…”

Section: Paf1c and Carm1 Coordinately Regulate A Common Set Of Erαmentioning

confidence: 99%

See 1 more Smart Citation

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

2012

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

View full text Add to dashboard Cite

The histone coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for a number of transcription factors, including nuclear receptors. Although CARM1 and its asymmetrically deposited dimethylation at histone H3 arginine 17 (H3R17me2a) are associated with transcription activation, the mechanism by which CARM1 activates transcription remains unclear. Using an unbiased biochemical approach, we discovered that the transcription elongation-associated PAF1 complex (PAF1c) directly interacts with H3R17me2a. PAF1c binds to histone H3 tails harboring dimethylation at R17 in CARM1-methylated histone octamers. Knockdown of either PAF1c subunits or CARM1 affected transcription of CARM1-regulated, estrogen-responsive genes. Furthermore, either CARM1 knockdown or CARM1 enzyme-deficient mutant knockin resulted in decreased H3R17me2a accompanied by the reduction of PAF1c occupancy at the proximal promoter estrogen-responsive elements. In contrast, PAF1c knockdown elicited no effects on H3R17me2a but reduced the H3K4me3 level at estrogen-responsive elements. These observations suggest that, apart from PAF1c's established roles in directing histone modifications, PAF1c acts as an arginine methyl histone effector that is recruited to promoters and activates a subset of genes, including targets of estrogen signaling.estrogen receptor-α | histone arginine methylation | PRMT

show abstract

Section: Paf1c and Carm1 Coordinately Regulate A Common Set Of Erαsupporting

confidence: 83%

Section: Paf1c and Carm1 Coordinately Regulate A Common Set Of Erαmentioning

confidence: 99%

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

2012

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

View full text Add to dashboard Cite

show abstract

“…hPAF1 was shown to be required for H2B ubiquitylation, as the RNF20/RNF40 complex associates with Pol II through binding to hPAF1 [69]. It was recently shown that TFIIS binds directly to both RNA Pol II and hPAF1, and the direct interaction between hPAF1 and TFIIS results in their cooperative binding to RNA Pol II, exerting a strong synergistic effect on transcription elongation [68]. In line with these observations, the catalytic activity of the RNF20-RNF40-hRAD6A complex was found to interfere with TFIIS binding to the hPAF1 complex, presumably through H2B ubiquitylation (see model in Fig.…”

Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

“…hPAF1 is an RNA Pol II-associated factor that facilitates transcription elongation [68]. hPAF1 was shown to be required for H2B ubiquitylation, as the RNF20/RNF40 complex associates with Pol II through binding to hPAF1 [69].…”

Section: Monoubiquitylated Histone H2bmentioning

confidence: 99%

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

View full text Add to dashboard Cite

a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

show abstract

“…Yeast PAFc is comprised of five subunits, including Paf1, Ctr9, Cdc73 (also known as parafibromin), Leo1, and Rtf1 (Jaehning 2010). PAFc plays a regulatory role during transcriptional initiation, elongation, and termination (Jaehning 2010; Kim et al 2010;Crisucci and Arndt 2011). PAFc has been well characterized for its role in controlling transcription-coupled histone modifications such as histone H2B monoubiquitination (H2Bub1), H3K4 trimethylation (H3K4me3), and H3K36me3 via interacting with the respective histone-modifying enzymes (Tomson and Arndt 2013).…”

mentioning

confidence: 99%

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

Zeng

2015

Genes Dev.

View full text Add to dashboard Cite

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.

show abstract

The Human PAF1 Complex Acts in Chromatin Transcription Elongation Both Independently and Cooperatively with SII/TFIIS

Cited by 227 publications

References 59 publications

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

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

Contact Info

Product

Resources

About