MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation

Summary The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.

• Publication year

  2019

• Venue

  Molecules and Cells

• Publication date

  2019-05-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.molcel.2019.02.031PMID 30928206PMCID 6527870
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2017cited by this paper
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  2017cited by this paper
• The Biogenesis of Nascent Circular RNAs.

  2016cited by this paper
• Different promoter affinities account for specificity in MYC-dependent gene regulation

  2016influential reference
• deepTools2: a next generation web server for deep-sequencing data analysis

  2016cited by this paper
• Ubiquitin-Dependent Turnover of MYC Antagonizes MYC/PAF1C Complex Accumulation to Drive Transcriptional Elongation.

  2016cited by this paper
• The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity.

  2016cited by this paper
• MYC: connecting selective transcriptional control to global RNA production

  2015cited by this paper
• THZ1 Reveals Roles for Cdk7 in Co-transcriptional Capping and Pausing.

  2015cited by this paper
• Taming of the beast: shaping Myc-dependent amplification.

  2015cited by this paper
• Getting up to speed with transcription elongation by RNA polymerase II

  2015cited by this paper
• BEDTools: The Swiss‐Army Tool for Genome Feature Analysis

  2014influential reference
• Cyclin-Dependent Kinase 7 Controls mRNA Synthesis by Affecting Stability of Preinitiation Complexes, Leading to Altered Gene Expression, Cell Cycle Progression, and Survival of Tumor Cells

  2014cited by this paper
• Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis

  2014cited by this paper
• MalaCards: A Comprehensive Automatically‐Mined Database of Human Diseases

  2014cited by this paper
• Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles

  2014influential reference
• Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

  2014influential reference
• Quantitative ChIP-Seq normalization reveals global modulation of the epigenome.

  2014cited by this paper
• RECQL5 Controls Transcript Elongation and Suppresses Genome Instability Associated with Transcription Stress

  2014cited by this paper
• 4sUDRB-seq: measuring genomewide transcriptional elongation rates and initiation frequencies within cells

  2014cited by this paper
• MYC activation is a hallmark of cancer initiation and maintenance.

  2014cited by this paper
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases

  2014influential reference
• Characterization of molecular and cellular functions of the cyclin‐dependent kinase CDK9 using a novel specific inhibitor

  2014cited by this paper
• Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

  2013cited by this paper
• Transitions for regulating early transcription.

  2013cited by this paper
• Global regulation of promoter melting in naive lymphocytes.

  2013cited by this paper
• Signaling pathways differentially affect RNA polymerase II initiation, pausing, and elongation rate in cells.

  2013cited by this paper
• An optimized microRNA backbone for effective single-copy RNAi.

  2013cited by this paper
• Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans

  2012cited by this paper
• MYC on the path to cancer.

  2012cited by this paper
• Cyclin-dependent kinase control of the initiation-to-elongation switch of RNA polymerase II

  2012cited by this paper
• Defining the status of RNA polymerase at promoters.

  2012cited by this paper
• A quantitative atlas of polyadenylation in five mammals

  2012cited by this paper
• Transcriptional amplification in tumor cells with elevated c-Myc.

  2012cited by this paper
• NIH Image to ImageJ: 25 years of image analysis

  2012cited by this paper
• c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.

  2012cited by this paper
• Vezf1 protein binding sites genome-wide are associated with pausing of elongating RNA polymerase II

  2012cited by this paper
• Metabolic labeling of RNA uncovers principles of RNA production and degradation dynamics in mammalian cells

  2011cited by this paper
• The Initiation Factor TFE and the Elongation Factor Spt4/5 Compete for the RNAP Clamp during Transcription Initiation and Elongation

  2011cited by this paper
• c-Myc regulates transcriptional pause release.

  2010influential reference
• The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.

  2010cited by this paper
• Spt6 enhances the elongation rate of RNA polymerase II in vivo

  2009cited by this paper
• Ultrafast and memory-efficient alignment of short DNA sequences to the human genome

  2009cited by this paper
• A RECQ5–RNA polymerase II association identified by targeted proteomic analysis of human chromatin

  2008cited by this paper
• MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification

  2008cited by this paper
• Modelling Myc inhibition as a cancer therapy

  2008cited by this paper
• Distinct thresholds govern Myc's biological output in vivo.

  2008cited by this paper
• Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo.

  2005cited by this paper
• c-Myc Mediates Activation of the cad Promoter via a Post-RNA Polymerase II Recruitment Mechanism*

  2001cited by this paper
• DSIF, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs.

  1998cited by this paper
• Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae.

  1998influential reference
• Regulation of TFIIH ATPase and kinase activities by TFIIE during active initiation complex formation

  1994cited by this paper
• SPT5, an essential gene important for normal transcription in Saccharomyces cerevisiae, encodes an acidic nuclear protein with a carboxy-terminal repeat

  1991influential reference
• SPT5, an essential gene important for normal transcription in Saccharomyces cerevisiae, encodes an acidic nuclear protein with a carboxy-terminal repeat

  1991cited by this paper

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  2026cites this paper
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  2025cites this paper
• A SETD2–CDK1–lamin axis maintains nuclear morphology and genome stability

  2025influential citation
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  2025cites this paper
• MYC: The Guardian of Its Own Chaos

  2025cites this paper
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  2025cites this paper
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  2025cites this paper
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  2025cites this paper
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  2025cites this paper
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  2023cites this paper
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  2023cites this paper
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  2023cites this paper
• Promoter-proximal regulation of gene transcription: Key factors involved and emerging role of general transcription factors in assisting productive elongation.

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  2022cites this paper
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  2022cites this paper
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  2022cites this paper
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  2022cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
• Gene Transactivation and Transrepression in MYC-Driven Cancers

  2021cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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