A sequence-specific core promoter-binding transcription factor recruits TRF2 to coordinately transcribe ribosomal protein genes

Baumann, Douglas G.; Gilmour, David S.

doi:10.1093/nar/gkx676

Cited by 42 publications

(72 citation statements)

References 42 publications

(97 reference statements)

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“…To better understand how TRF2 regulates the expression of the cyclin genes, we turned our attention to TRF2-interacting proteins. TRF2 was recently shown to interact with M1BP (motif 1 binding protein) (57). Interestingly, M1BP was recently demonstrated to interact with GFZF, a nuclear glutathione S-transferase protein that has been implicated in cell cycle regulation (58).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, using FLAG immuno-affinity purification from FLAG-HA TRF2-inducible S2R+ cells followed by mass spectrometry analysis, we discovered that both M1BP and GFZF are in complex with the evolutionarily conserved TRF2 (also known as short TRF2), but not with the long Drosophila -only TRF2 isoform or with TBP (Table 3 and Additional file 8: Table S3). This prompted us to examine the occupancy of TRF2, M1BP and GFZF in the vicinity of the TSSs (−100 to +100 relative to the TSS) of TRF2-regulated cyclin genes, using publicly available TRF2, M1BP and GFZF ChIP-exo analyses in Drosophila S2R+ cells (GSE97841, GSE105009) (57, 58). We examined the number of bound sites, the average peak scores and the maximum peak scores of cyclin genes and several ribosomal protein genes for comparison (Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…b Top enriched motif among the 4331 commonly bound promoters, as detected by MEME analysis. Its resemblance to Ohler Motif 1 is depicted by the motif logo derived by M1BP ChIP-exo (57). c The 4331 commonly bound regions were analyzed for core promoter composition.…”

Section: Resultsmentioning

confidence: 99%

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The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

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26Background: Diverse biological processes and transcriptional programs are 27 regulated by RNA polymerase II (Pol II), which is recruited by the general transcription 28 machinery to the core promoter to initiate transcription. TRF2 (TATA-box-binding 29 protein-related factor 2) is an evolutionarily conserved general transcription factor that 30 is essential for embryonic development of Drosophila melanogaster, C. elegans, 31 zebrafish and Xenopus. Nevertheless, the cellular processes that are regulated by 32 TRF2 are largely underexplored. 33Results: Here, using Drosophila Schneider cells as a model, we discovered that TRF2 34 regulates apoptosis and cell cycle progression. We show that TRF2 knockdown 35 results in increased expression of distinct pro-apoptotic genes and induces apoptosis. 36Using flow cytometry, high-throughput microscopy and advanced imaging-flow 37 cytometry, we demonstrate that TRF2 regulates cell cycle progression and exerts 38 distinct effects on G1 and specific mitotic phases. RNA-seq analysis revealed that 39 TRF2 controls the expression of Cyclin E and the mitotic cyclins, Cyclin A, Cyclin B 40 and Cyclin B3, but not Cyclin D or Cyclin C. To identify proteins that could account for 41 the observed regulation of these cyclin genes, we searched for TRF2-interacting 42 proteins. Interestingly, mass spectrometry analysis of TRF2-containing complexes 43 identified GFZF, a nuclear glutathione S-transferase implicated in cell cycle regulation, 44and Motif 1 binding protein (M1BP). TRF2 has previously been shown to interact with 45 M1BP and M1BP has been shown to interact with GFZF. Furthermore, available ChIP-46 exo data revealed that TRF2, GFZF and M1BP co-occupy the promoters of TRF2-47 with TRF2, it is TRF2, rather than GFZF or M1BP, that is the main factor regulating 50 the expression of Cyclin E and the mitotic cyclins. 51 Conclusions: Our findings uncover a critical and unanticipated role of a general 52 transcription factor as a key regulator of cell cycle and apoptosis. 53 54 Keywords 55 Basal transcription machinery, RNA polymerase II, gene expression, TATA box-56 binding protein (TBP), TBP-related factor 2 (TRF2), cyclin genes. 57 58 BACKGROUND 59 Multiple biological processes and transcriptional programs are regulated by RNA 60 polymerase II (Pol II). The initiation of transcription of protein-coding genes and 61 distinct non-coding RNAs occurs following the recruitment of Pol II to the core 62 promoter region by the general/basal transcription machinery (1-4). The core 63promoter, which directs accurate initiation of transcription and encompasses the 64 transcription start site (TSS), may contain short DNA sequence elements/motifs, 65 which confer specific properties to the core promoter (1, 4-10). The first step in the 66 recruitment of Pol II to initiate transcription is the binding of TFIID, which is 67 composed of TATA-box-binding protein (TBP) and TBP-associated factors. 68Remarkably, although TBP is considered a universal general transcription factor, 69 robust Pol II transc...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

Kedmi

Sloutskin

Epstein

et al. 2020

Preprint

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“…To evaluate this prediction and define factors that might contribute to this behavior, we computationally assessed a comprehensive repertoire of ChIP-seq data (Baumann and Gilmour, 2017;Henriques et al, 2018;Ho et al, 2014;Kaye et al, 2018;modENCODE Consortium et al, 2010;Weber et al, 2014). Specifically, we sought to identify factors enriched (or de-enriched) at gene promoters where pausing is unstable as compared to other promoters (see Methods).…”

Section: Resultsmentioning

confidence: 99%

“…A comprehensive repertoire of ChIP-seq datasets from (Baumann and Gilmour, 2017;Henriques et al, 2018;Kaye et al, 2018;Lim et al, 2013;Weber et al, 2014) and…”

Section: Features Associated With Genes With Short-lived Promoter Polmentioning

confidence: 99%

The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Elrod

Henriques

Huang

et al. 2019

Preprint

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Highlights:• The Integrator complex inhibits transcription elongation at ~15% of mRNA genes• Integrator targets promoter-proximally paused Pol II for termination• The RNA endonuclease of Integrator subunit 11 is critical for gene attenuation • Integrator-repressed genes are enriched in signaling and growth-responsive pathways SUMMARY The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25-60 nucleotide-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, a number of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA.Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.

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Process Development of Protein Therapeutics

Huang¹,

Bowes²,

Yang³

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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The application of recombinant DNA technology to the production of protein therapeutics has undergone tremendous progress over the past decades. Considerable scientific effort has been devoted to developing robust processes that produce large amounts of complex proteins with the desired product quality attributes. An overview of the contributions from the four major disciplines working in concert to deliver these processes and methods will be covered. This article will discuss some of the tools, methods, and approaches used to produce, purify, formulate, and analyze the drugs of modern biotechnology. Future trends in each of the disciplines will also be presented.

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A sequence-specific core promoter-binding transcription factor recruits TRF2 to coordinately transcribe ribosomal protein genes

Cited by 42 publications

References 42 publications

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

The TRF2 General Transcription Factor Is a Key Regulator of Cell Cycle Progression

The Integrator complex terminates promoter-proximal transcription at protein-coding genes

Process Development of Protein Therapeutics

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