Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpointm [RN21236 dTAG TTchem-seq]

ABSTRACT: The purpose and function of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remain uncertain. Here, we show that when Integrator function is compromised by loss of INTS6, RNAPII interacts increasingly with proteins from alternative pathways for its DNA dissociation, including CUL3-ARMC5 (CRL3ARMC5), which ubiquitylates Ser5-phosphorylated Rpb1 and targets it for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors required for correctly regulated promoter-proximal pausing, including Integrator, DSIF and mRNA capping enzyme. This ARMC5 checkpoint curtails an appreciable fraction of RNAPII transcription, with ARMC5 knockout cells producing uncapped, nascent RNA transcripts that fail to mature into stable mRNA. Concomitant loss of INTS6 and ARMC5 greatly stabilizes RNAPII at the pause and has severe consequences for cell growth and viability. Our data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253354 | GEO | 2024/11/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpoint [RN21114 Ttchemn-Seq]

Project description:The purpose and function of Integrator and RNA polymerase II (RNAPII) promoter-proximal pausing remain uncertain. Here, we show that when Integrator function is compromised by loss of INTS6, RNAPII interacts increasingly with proteins from alternative pathways for its DNA dissociation, including CUL3-ARMC5 (CRL3ARMC5), which ubiquitylates Ser5-phosphorylated Rpb1 and targets it for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors required for correctly regulated promoter-proximal pausing, including Integrator, DSIF and mRNA capping enzyme. This ARMC5 checkpoint curtails an appreciable fraction of RNAPII transcription, with ARMC5 knockout cells producing uncapped, nascent RNA transcripts that fail to mature into stable mRNA. Concomitant loss of INTS6 and ARMC5 greatly stabilizes RNAPII at the pause and has severe consequences for cell growth and viability. Our data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.

2024-11-05 | GSE253353 | GEO

Distinct pathways for removal of defective RNA polymerase II transcription complexes at a promoter-proximal pause checkpoint

Project description:The Integrator complex interacts with RNA polymerase II (RNAPII) at promoter-proximal pause sites but its function there remains uncertain. Here, we show that when Integrator function is compromised by loss of INTS6, RNAPII interacts increasingly with proteins that mediate its dissociation from DNA, including CUL3-ARMC5, which ubiquitylates Ser5-phosphorylated Rpb1 and targets it for degradation. ARMC5-dependent RNAPII ubiquitylation is activated by defects in factors required for correctly regulated promoter-proximal pausing, including Integrator, DSIF and mRNA capping enzyme. This ARMC5 checkpoint curtails an appreciable fraction of RNAPII transcription, with ARMC5 knockout cells producing uncapped, nascent RNA transcripts that fail to mature into stable mRNA. Concomitant loss of INTS6 and ARMC5 greatly stabilizes RNAPII at the pause and has severe consequences for cell growth and viability. Our data support a model in which CRL3ARMC5 functions alongside Integrator in a checkpoint mechanism that removes faulty RNAPII complexes at promoter-proximal pause sites to safeguard transcription integrity.

2024-11-05 | GSE251941 | GEO

ARMC5-mediated degradation of RNA polymerase II as a last resort in the promoter-proximal pausing checkpoint [TTchem-Seq]

Project description:RNA polymerase II (RNAPII) promoter-proximal pausing is an early step in the transcription cycle, which occurs alongside important events such as mRNA capping. Here, we identify a ubiquitin ligase complex, CUL3-ARMC5 (CRL3ARMC5) which is required for targeting promotor-proximally paused RNAPII for degradation. While a basal level of ARMC5-dependent RNAPII ubiquitylation/degradation occurs even in unperturbed cells, depletion of proteins regulating promoter-proximal pausing results in markedly increased ubiquitylation. We suggest that such RNAPII ubiquitylation/degradation serves as a “last resort” pathway for removing inept polymerases at a promoter-proximal pause checkpoint to avoid their release for unproductive transcript elongation. In agreement with this idea, ARMC5 knockout cells display increased levels of nascent transcription but with pre-mRNAs exhibiting capping defects. Together, our findings support a model in which promoter-proximal pausing functions as a transcription cycle checkpoint and indicate broad role for the CRL3ARMC5 ligase in RNAPII poly-ubiquitylation and degradation.

2024-11-05 | GSE219075 | GEO

ARMC5-mediated degradation of RNA polymerase II as a last resort in the promoter-proximal pausing checkpoint [RNA-Seq]

2024-11-05 | GSE219074 | GEO

ARMC5-mediated degradation of RNA polymerase II as a last resort in the promoter-proximal pausing checkpoint [PRO-seq]

2024-11-05 | GSE219073 | GEO

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9

Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclindependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPIICTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLLrearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that finely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

2022-08-12 | PXD022962 | Pride

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [ChIP-seq]

Project description:Gene expression by RNA Polymerase II (RNAPII) is tightly controlled by Cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The RNAPII pausing checkpoint, engaged after transcription initiation, is controlled by CDK9 to regulate transcription in metazoans. We discovered that CDK9-mediated RNAPII pause-release is functionally opposed by a protein phosphatase 2A (PP2A) complex. PP2A dynamically competes for key CDK9 substrates, DSIF and RNAPII-CTD, and is recruited to transcription pausing sites by the Integrator complex subunit INTS6. INTS6 depletion confers resistance to CDK9 inhibition in a variety of normal and tumor cell lines. Loss of INTS6 abolishes the Integrator-PP2A association leading to unrestrained CDK9 activity, which amplifies transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill MLL-rearranged leukemias and solid tumors and provide therapeutic benefit in vivo. These data demonstrate that f inely-tuned gene expression relies on the balance of kinase and phosphatase activity at the pausing checkpoint.

2021-05-23 | GSE163804 | GEO

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [4sU-seq]

2021-05-23 | GSE163803 | GEO

A PP2A-Integrator complex fine-tunes transcription by opposing CDK9 [3UTR-seq]

2021-05-23 | GSE163802 | GEO

Integrator complex regulates NELF-mediated RNA Polymerase II pause/release and processivity at coding genes [RNA-seq]

Project description:RNAPII pausing/termination shortly after initiation is a hallmark of gene regulation. However, the molecular mechanisms involved are still to be uncovered. Here, we show that NELF interacts with Integrator complex subunits (INTScom) forming a stable complex with RNPII and Spt5. The interaction between NELF and INTScom subunits is RNA and DNA independent. Using both HIV-1 promoter and genome wide analyses, we demonstrate that Integrator subunits specifically control NELF-mediated RNAPII pause/release at coding genes. The strength of RNAPII pausing is determined by the nature of the NELF-associated complex. Interestingly, in addition to controlling RNAPII pause release INTS11 catalytic subunit of the INTScom is required for the synthesis of full length mRNA. Finally, INTScom-target genes are enriched in HIV-1 TAR/ NELF-binding element and in a 3’box sequence required for snRNA biogenesis. Revealing these unexpected functions of INTScom in regulating RNAPII pausing/release and completion of mRNA synthesis of NELF-target genes will contribute to our understanding of the gene expression cycle. Genome-wide expression in HeLa cells in the absence of Integrator 11, or NELF or mock (control) depleted by strand-specific RNASeq (Illumina)

2015-05-19 | E-GEOD-60585 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data