TFIIH Operates through an Expanded Proximal Promoter To Fine-Tune c<i>-myc</i> Expression

Weber, Achim; Liu, Juhong; Collins, Irene; Levens, David

doi:10.1128/mcb.25.1.147-161.2005

Cited by 58 publications

(62 citation statements)

References 78 publications

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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.…”

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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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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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“…56 The increased variation in Myc expression elicited by FBP KO mirrors the variation in MYC levels seen in XP. 6 In XPB disease, the responses of the 3 0 to 5 0 p89/XPB helicase of TFIIH to effector domains of FBP and FIR are mutationally disabled, and the output of MYC is buffeted by the changes in the flux of the pathways that converge onto the MYC locus at the level of the chromatin and transcription machineries.…”

Section: Discussionmentioning

confidence: 99%

“…6 Similarly, the FBP/FIR/FUSE system acts through this subunit and is proposed to act as a molecular cruise control to dampen fluctuations in MYC expression. 4,5,7,10 If this proposal has merit, then Myc levels in Fubp1 À/À cells should vary more than in WT cells.…”

Section: Lacking Fbp Myc Is Dysregulatedmentioning

confidence: 99%

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Zhou

Chung

Castellar

et al. 2016

The American Journal of Pathology

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The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1 À/À ) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1 À/À hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1 À/À hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1 À/À embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression. The transcription factor Myc plays a decisive role in cell growth, differentiation, and senescence and so must be highly regulated. The far upstream element (FUSE) binding protein (FBP) binds single-stranded DNA of FUSE 1.7 kb upstream of the major P2 promoter of the human MYC gene. 1e3 FUSE melting in response to dynamic supercoils propagated from the MYC promoters enables FBP binding. FBP activates TFIIH helicase activity to accelerate the transcription cycle from preinitiation complex assembly through promoter escape and onto pause release. 4e6 Positive regulation of MYC is at least in part counteracted by FBP interacting repressor (FIR) that binds FBP and FUSE and opposes TFIIH helicase activity, retarding the transcription cycle. 5,7 Besides MYC, FBP regulates the expression of the cyclin-dependent kinase inhibitor p21, stathmin, and USP29, a powerful stabilizer of p53 induced by oxidative stress. 8e10 Because the FBP/FIR system reads single-stranded DNA sequences exposed by transcriptionally generated dynamic supercoiling, it is proposed that the FBP/ FIR/FUSE system serves as a molecular cruise control that monitors the mechanical output of promoters in real time while providing both positive and negative feedback. 11e13Supported by the NIH

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“…4,15); therefore, P89 expression should be critical for c-myc regulation through FIR (4,16). This study revealed that both total FIRs (authentic FIR and FIR splicing variants including FIRDexon2) and P89 expression were significantly activated in colorectal cancer tissues (T) compared with corresponding nontumor tissues (N; Fig.…”

Section: Tfiih/p89/ercc3/xpb Is Activated In Colon Cancer Tissuesmentioning

confidence: 93%

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

Matsushita

Tamura

Tanaka

et al. 2013

Molecular Cancer Research

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Oncogenic c-Myc plays a critical role in cell proliferation, apoptosis, and tumorigenesis, but the precise mechanisms that drive this activity remain largely unknown. P27Kip1 (CDKN1B) arrests cells in G1, and SAP155 (SF3B1), a subunit of the essential splicing factor 3b (SF3b) subcomplex of the spliceosome, is required for proper P27 pre-mRNA splicing. FUSE-binding protein-interacting repressor (FIR), a splicing variant of PUF60 lacking exon5, is a c-Myc transcriptional target that suppresses the DNA helicase p89 (ERCC3) and is alternatively spliced in colorectal cancer lacking the transcriptional repression domain within exon 2 (FIRDexon2). FIR and FIRDexon2 form a homo-or hetero-dimer that complexes with SAP155. Our study indicates that the FIR/FIRDexon2/SAP155 interaction bridges c-Myc and P27 expression. Knockdown of FIR/FIRDexon2 or SAP155 reduced p27 expression, inhibited its pre-mRNA splicing, and reduced CDK2/ Cyclin E expression. Moreover, spliceostatin A, a natural SF3b inhibitor, markedly inhibited P27 expression by disrupting its pre-mRNA splicing and reduced CDK2/Cyclin E expression. The expression of P89, another FIR target, was increased in excised human colorectal cancer tissues. Knockdown of FIR reduced P89; however, the effects on P27 and P89 expression are not simply or directly related to altered FIR expression levels, indicating that the mechanical or physical interaction of the SAP155/FIR/FIRDexon2 complex is potentially essential for sustained expression of both P89 and P27. Together, the interaction between SAP155 and FIR/ FIRDexon2 not only integrates cell-cycle progression and c-Myc transcription by modifying P27 and P89 expression but also suggests that the interaction is a potential target for cancer screening and treatment. Mol Cancer Res; 11(7); 689-98. Ó2013 AACR.

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TFIIH Operates through an Expanded Proximal Promoter To Fine-Tune c-myc Expression

Cited by 58 publications

References 78 publications

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

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

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

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