Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and is expressed in a strictly growth factor-dependent manner in non-tumor cells. Here we show that MYC directly binds SPT5, a subunit of the RNA polymerase II (POL2) elongation factor DSIF. MYC recruits SPT5 to genes and enables the CDK7-dependent transfer of SPT5 onto POL2. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. In addition, MYC increases the directionality of promoters by stimulating sense transcription and suppressing the synthesis of antisense RNAs. Our results argue that MYC controls the productive assembly of POL2 with general elongation factors to form processive elongation complexes. The high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, slows transcription at growth-suppressive genes and promotes uncontrolled cellular growth.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115365 | GEO | 2019/03/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Project description:MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation

| PRJNA474714 | ENA

Regulation of RNA polymerase II processivity by Spt5 is restricted to a narrow window in elongation

Project description:Spt5 is a highly conserved RNA polymerase II (Pol II)-associated pausing and elongation factor. However, its impact on global elongation and Pol II processivity in mammalian cells has not been clarified. Here, we show that depleting Spt5 in mouse embryonic fibroblasts (MEFs) does not cause global elongation defects or decreased elongation rates. Instead, in the absence of Spt5, a fraction of Pol II molecules are dislodged during elongation thus decreasing the number of Pol II complexes that complete the transcription cycle. Most strikingly, this decrease is restricted to a narrow window between 15-20 kb from the promoter, a distance which coincides with the stage where accelerating Pol II attains maximum elongation speed and processivity. Consequently, long genes show a greater dependency on Spt5 for optimal elongation efficiency and overall gene expression than short genes. We propose that an important role of Spt5 in mammalian elongation is to promote the processivity of those Pol II complexes that are transitioning towards maximum elongation speed 15-20 kb from the promoter.

2018-03-06 | GSE106313 | GEO

siRNA profiling of Zebrafish embryos knocked down for Spt5

Project description:The Spt4-Spt5 complex, and its human homolog DSIF (DRB sensitivity-inducing factor), is unique in its ability to regulate Pol II processivity. Previous studies have shown that Spt5 has the characteristics of a general transcription-elongation factor. However, mutagenesis of Spt5 showed specific phenotypes during development, which were far less severe than those of Pol II defects or TBP deficient embryos. It seems paradoxical that a mutation which alters a general elongation factor can cause rather specific developmental defects. By using Spt5 knockdown zebrafish embryos and microarrays, here we showed that transcript abundance for only a small subset of genes is altered by loss of Spt5. Further investigation of the down-regulated genes showed that the genes most intensely repressed by the knockdown were strongly activated during early development in untreated embryos. Thus, this study shows that gene activation levels may create different requirements for Pol II processivity. Active transcription requires Spt5 for efficient elongation through its stimulatory activity on Pol II processivity. Experiment Overall Design: The expression pattern of Spt5 knockdown embryos was compared to that of the control mopholino oligo injected embryos, both at 21 hours post-fertilization, to show the targets of Spt5. The activation levels of the Spt5-knockdown affected genes were measured by compareing the abundance of transcripts in 21 hours post-fertilization untreated embryos to that in 5 hours post-fertilization untreated embryos.

2008-06-14 | E-GEOD-6127 | biostudies-arrayexpress

The Myc binding partner Spt5 is essential for brain tumor growth in Drosophila

Project description:The transcription factor SPT5 physically interacts with MYC oncoproteins and is essential for the full transcriptional activation of MYC targets in cultured cells. Here, we use Drosophila to show that SPT5 is also required for MYC-dependent processes in vivo. Depletion of SPT5 strongly impairs the growth of a model neuronal tumor and substantially extends survival of tumor-bearing animals. This beneficial effect is also observed when SPT5 is knocked down systemically after tumor initiation, highlighting SPT5 is a potential drug target in human oncology.

2023-10-23 | GSE220110 | GEO

The pausing zone and control of RNA polymerase II elongation by Spt5: implications for the pause-release model

Project description:The pause-release model of transcription proposes that pol II pauses 40-100 bases from the start site resulting in a pile-up that is relieved by subsequent release into productive elongation. Pause release is facilitated by PTEFb phosphorylation of the pol II elongation factor, Spt5. We mapped paused polymerases by eNETseq and found frequent pausing in zones that extend ~0.3-3kb into genes, even when PTEFb is inhibited. The fraction of paused polymerases or “pausiness” declines gradually over several kb, and not abruptly as predicted for a discrete pause release event. Spt5 depletion extends pausing zones suggesting that it promotes maturation of elongation complexes to a low-pausing state. Expression of mutants after Spt5 depletion showed that phosphomimetic substitutions in the Spt5 CTR1 domain diminished pausing throughout genes. In contrast mutants that prevent phosphorylation of the Spt5 RNA-binding domain strengthened pausing. Thus distinct Spt5 phospho-isoforms set the balance between pausing and elongation.

2022-10-01 | GSE202749 | GEO

The expression of Spt5 targeted genes

Project description:The Spt4-Spt5 complex, and its human homolog DSIF (DRB sensitivity-inducing factor), is unique in its ability to regulate Pol II processivity. Previous studies have shown that Spt5 has the characteristics of a general transcription-elongation factor. However, mutagenesis of Spt5 showed specific phenotypes during development, which were far less severe than those of Pol II defects or TBP deficient embryos. It seems paradoxical that a mutation which alters a general elongation factor can cause rather specific developmental defects. By using Spt5 knockdown zebrafish embryos and microarrays, here we showed that transcript abundance for only a small subset of genes is altered by loss of Spt5. Further investigation of the down-regulated genes showed that the genes most intensely repressed by the knockdown were strongly activated during early development in untreated embryos. Thus, this study shows that gene activation levels may create different requirements for Pol II processivity. Active transcription requires Spt5 for efficient elongation through its stimulatory activity on Pol II processivity. Keywords: Spt5, microarray analysis, development, transcription, transcription elongation

2007-10-25 | GSE6127 | GEO

Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy

Project description:The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.

2018-10-26 | GSE112608 | GEO

Genome-wide analyses reveal widespread roles for Spt5 in sense and antisense transcription [ChIP-seq_round2]

Project description:Many proteins associate with elongating RNA polymerase II (RNAPII), although the functions of most of them are still not well understood. Spt5 is an essential transcription elongation factor that binds directly to RNA polymerase and is conserved in prokaryotes, archaea, and eukaryotes1. In eukaryotes, evidence suggests that Spt5 functions in transcription elongation by both RNA polymerases I and II, mRNA capping, mRNA splicing, and mRNA 3’ end formation2. However, the genome-wide requirement for Spt5 in transcription has not been extensively studied. To address this issue, we have comprehensively analyzed the consequences of Spt5 depletion on transcription by RNAPII in Schizosaccharomyces pombe using four genome-wide approaches: ChIP-seq, NET-seq, 4tU-seq, and RNA-seq. Our results demonstrate that, in the absence of Spt5, RNAPII accumulates at a high level over the first ~500 bp of transcription units, suggesting that Spt5 is globally required to elongate past a barrier to transcription. This possibility is strongly supported by results showing that Spt5 is required for a normal level of RNA synthesis. In addition to these effects on sense-strand transcription, Spt5 depletion results in widespread convergent antisense transcription that initiates at approximately the same position as the sense-strand barrier. While the role of these antisense transcripts is unknown, the two that were tested control the distribution of RNAPII. Our results also show that Spt5 represses divergent antisense transcription, explaining why it has not been previously observed in S. pombe. Taken together, our results reveal a global and critical role for Spt5 in multiple classes of transcription by RNAPII.

2017-03-30 | GSE93803 | GEO

Genome-wide analyses reveal widespread roles for Spt5 in sense and antisense transcription [RNA-seq]

2017-03-30 | GSE85125 | GEO

Genome-wide analyses reveal widespread roles for Spt5 in sense and antisense transcription [4tU-seq]

2017-03-30 | GSE85181 | GEO