The repetitive C‐terminal domain of RNA polymerase II: Multiple conformational states drive the transcription cycle

Lin, Patrick S.; Tremeau‐Bravard, Alexandre; Dahmus, Michael E.

doi:10.1002/tcr.10063

Cited by 6 publications

(5 citation statements)

References 81 publications

(82 reference statements)

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“…The C-terminal domain (CTD) is composed of 52 tandem repeats of heptapeptide YSPTSPS that are subject to phosphorylation. The two major phosphorylation sites of Pol II are Ser2 and Ser5; phosphorylation at these sites results in two forms of Pol II (hypophosphorylated IIa and hyperphosphorylated IIo) (28). In the process of transcription initiation, the predominant phosphorylation of Pol II is on Ser5, while in transcription elongation, the major form is Ser2 phosphorylation (9).…”

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confidence: 99%

Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription

Shah

Chang

et al. 2004

Molecular and Cellular Biology

113

147

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Transcriptional activation of eukaryotic genes depends on the precise and ordered recruitment of activators, chromatin modifiers/remodelers, coactivators, and general transcription factors to the promoters of target genes. Using the human matrix metalloproteinase 9 (MMP-9) gene as a model system, we investigated the sequential assembly and dynamic formation of transcription complexes on a human promoter under the influence of mitogen signaling. We find that, coincident with activation of the MMP-9 gene, activators, chromatin remodeling complexes, and coactivators are recruited to the preassembled MMP-9 promoter in a stepwise and coordinated order, which is dependent on activation of MEK-1/extracellular signal-regulated kinase and NF-B signaling pathways. Conversely, corepressor complexes are released from the MMP-9 promoter after transcriptional activation. Histone modifications shift from repressive to permissive modifications concurrent with activation of the MMP-9 gene. Chromatin remodeling induced by Brg-1 is required for MMP-9 gene transcription, which is concomitant with initiation of transcription. Therefore, coordination of cell signaling, chromatin remodeling, histone modifications, and stepwise recruitment of transcription regulators is critical to precisely regulate MMP-9 gene transcription in a temporally and spatially dependent manner. Given the important role of MMP-9 in both normal development and pathological conditions, understanding MMP-9 gene regulation is of great relevance.Gene transcription in eukaryotic cells is controlled by protein complexes, including general and tissue-specific transcription factors, coregulators, chromatin-remodeling complexes, and complexes responsible for signal-specific histone modifications (26). As eukaryotic DNA is packaged into chromatin, generally a repressive structure for transcriptional activation, transcription in the context of chromatin requires remodeling processes to reconfigure the chromatin, so that activators, coactivators, and general transcription factors (GTFs) have access to promoters of target genes (12). Chromatin remodeling is dependent on either ATP-dependent chromatin-remodelingcomplex-induced structural modifications of nucleosomes or histone acetyltransferase-(HAT) and histone methyltransferase-mediated covalent modifications of the N-terminal tails of core histones (12). The SWI/SNF chromatin-remodeling complex can alter chromatin structure by either shifting nucleosomes along the DNA or twisting DNA to modulate the nucleosome structure (42). Brg-1 and Brm are two ATPase subunits of the SWI/SNF complex. Recruitment of the SWI/ SNF complex to target promoters requires protein-protein interactions through Brg-1 and other transcription regulators, as Brg-1 does not recognize sequence-specific DNA (21).

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confidence: 99%

Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription

Shah

Chang

et al. 2004

Molecular and Cellular Biology

113

147

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“…Each repeat contains two potential Ess1 binding sites (underlined). The heptad repeat within the CTD of Rpb1 is known to be reversibly phosphorylated in vivo, and these changes in phosphorylation are correlated with distinct steps in pol II transcription (initiation, elongation, and termination) and mRNA processing (capping, 3Ј cleavage, and polyadenylation (22,23)). Our genetic analyses, and those of Hani and colleagues, have shown that Ess1 is involved in multiple stages of transcription and mRNA processing (16,25,26,47 We have proposed a model in which Ess1 binds and isomerizes the CTD of Rpb1, thereby affecting cofactor binding to the pol II complex (16).…”

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Vanishingly Low Levels of Ess1 Prolyl-isomerase Activity Are Sufficient for Growth in Saccharomyces cerevisiae

Gemmill

Hanes

2005

Journal of Biological Chemistry

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Ess1 is an essential peptidylprolyl-cis/trans-isomerase in the yeast Saccharomyces cerevisiae. Ess1 and its human homolog, Pin1, bind to phospho-Ser-Pro sites within proteins, including the carboxyl-terminal domain (CTD) of Rpb1, the largest subunit of RNA polymerase II (pol II). Ess1 and Pin1 are thought to control mRNA synthesis by catalyzing conformational changes in Rpb1 that affect interaction of cofactors with the pol II transcription complex. Here we have characterized wild-type and mutant Ess1 proteins in vitro and in vivo. We found that Ess1 preferentially binds and isomerizes CTD heptad-repeat (YSPTSPS) peptides that are phosphorylated on Ser5. Binding by the mutant proteins in vitro was essentially normal, and the proteins were largely stable in vivo. However, their catalytic activities were reduced >1,000-fold. These data along with results of in vivo titration experiments indicate that Ess1 isomerase activity is required for growth, but only at vanishingly low levels. We found that although wildtype cells contain about ϳ200,000 molecules of Ess1, a level of fewer than 400 molecules per cell is sufficient for growth. In contrast, higher levels of Ess1 were required for growth in the presence of certain metabolic inhibitors, suggesting that Ess1 is important for tolerance to environmental challenge.

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“…Furthermore, extensive CTD phosphorylation in response to UV exposure has been proposed to reduce transcription initiation on an undamaged target gene in vitro, possibly by decreasing the pool of RNAPII competent for preinitiation complex assembly (24). The later observation may reflect the proposed dual role of CTD kinases, which is to act either as a specific positive transcription factor or in some circumstances as a general negative factor (25).…”

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confidence: 99%

The BRCA1 COOH-terminal Region Acts as an RNA Polymerase II Carboxyl-terminal Domain Kinase Inhibitor That Modulates p21 Expression

Moisan¹,

Gaudreau

2006

Journal of Biological Chemistry

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BRCA1 is involved both in positive and negative regulation of gene activity as well as in numerous other processes, such as DNA damage response and repair. We recently reported that BRCA1 inhibits RNA polymerase II carboxyl-terminal domain (CTD) phosphorylation by TFIIH and decreases serine 5 phosphorylation levels when introduced into a BRCA1 ؊/؊ cell line. Regulation of CTD phosphorylation is crucial for proper gene expression and response to cellular stresses, such as DNA damage and transcription arrest. A key player in this process, P-TEFb, phosphorylates the CTD on serine 2 of transcriptionally engaged RNA polymerase II, and its kinase activity was shown to be up-regulated when cells are exposed to transcriptional stress such as UV irradiation. Here, we investigate the effect of BRCA1 on serine 2 phosphorylation and UV-activated P-TEFb kinase activity. We now show that BRCA1 inhibits immunoprecipitated P-TEFb kinase activity from UV-irradiated cells and preferentially decreases UV-induced serine 2 phosphorylation of soluble, rather than chromatin-bound, RNAPII. We further show that BRCA1 rescues the UV-mediated inhibition of transcriptional activity from nuclear extracts and stimulates endogenous p21 gene expression upon UV irradiation, a function that is dependent of the inhibition of CTD kinase activity. Our results suggest that BRCA1 could act as a CTD kinase inhibitor and, as such, contribute to the regulation of p21 gene expression.Mutations in BRCA1 (breast cancer susceptibility gene 1) account for ϳ45% of reported cases of hereditary breast cancer. The BRCA1 protein acts as a tumor suppressor that plays a crucial role in the maintenance of genomic integrity. BRCA1 achieves this function by integrating important cellular processes, such as regulation of gene expression, the DNA damage response, and cell cycle control (1). For instance, BRCA1 can positively modulate the expression of the p21 (2) and GADD45 stress-responsive genes (2, 3), the DDB2 and XPC nucleotide excision repair genes (4) and the p27 (5) and 14-3-3 cell cycle arrest genes (5, 6). On the other hand, BRCA1 has also been shown to down-regulate the transcriptional activity elicited by the c-Myc proto-oncogene (7), as well as by ER-␣ (8). Importantly, BRCA1 co-purifies with a form of RNA polymerase II (RNAPII) holoenzyme by interacting with RNA helicase A (9) or by directly contacting the RPB2 and RPB10␣ subunits of core RNAPII (10). Interestingly, a biochemical study proposed that following replication blockage by hydroxyurea treatment, a fraction of RNAPII holoenzyme-bound BRCA1 shifts to a new complex that contains BARD1 (BRCA1-associated RING domain 1) (11). This is consistent with a previous finding that showed that BRCA1 is phosphorylated and relocalized from its nuclear foci to sites of DNA damage after treatment with UV light, hydroxyurea, or ␥-irradiations (12). Furthermore, a recent report revealed that the association of BRCA1 with processive RNAPII is abrogated when cells are subjected to various DNA-damaging agents (13).The R...

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The repetitive C‐terminal domain of RNA polymerase II: Multiple conformational states drive the transcription cycle

Cited by 6 publications

References 81 publications

Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription

Coordination of Cell Signaling, Chromatin Remodeling, Histone Modifications, and Regulator Recruitment in Human Matrix Metalloproteinase 9 Gene Transcription

Vanishingly Low Levels of Ess1 Prolyl-isomerase Activity Are Sufficient for Growth in Saccharomyces cerevisiae

The BRCA1 COOH-terminal Region Acts as an RNA Polymerase II Carboxyl-terminal Domain Kinase Inhibitor That Modulates p21 Expression

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