The small but versatile DSS1 protein is required for proper Integrator–PP2A function [CUT&Tag]
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ABSTRACT:
PROVIDER: PRJNA1262355 | ENA |
REPOSITORIES: ENA
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Project description:Integrator-PP2A (INTAC) is a highly modular complex orchestrating the transition of paused RNA polymerase II into productive elongation or promoter-proximal premature termination, with its loss resulting in transcription dysregulation and genome instability. Here, we identify human DSS1—a flexible 70-residue protein found in multiple functionally diverse complexes including the 26S proteasome—as an integral subunit of the INTAC backbone. Structural analysis of DSS1–INTAC, both alone and in association with paused polymerase, demonstrates intimate interactions between DSS1 and the INTAC backbone. We identify tryptophan 39 of DSS1 as being critical for interacting with INTAC and find that its mutation disrupts DSS1’s interaction with INTAC, while maintaining DSS1’s interaction with the proteasome. This substitution not only impairs INTAC-dependent transcriptional regulation, but also reveals that INTAC is DSS1’s major chromatin-bound form. Together, our findings reveal a role for the versatile DSS1 protein in supporting the structure and regulatory functions of INTAC.
2025-07-09 | GSE297000 | GEO
Project description:The small but versatile DSS1 protein is required for proper Integrator–PP2A function [ChIP-seq]
| PRJNA1262356 | ENA
Project description:Integrator-PP2A (INTAC) is a highly modular complex orchestrating the transition of paused RNA polymerase II into productive elongation or promoter-proximal premature termination, with its loss resulting in transcription dysregulation and genome instability. Here, we identify human DSS1—a flexible 70-residue protein found in multiple functionally diverse complexes including the 26S proteasome—as an integral subunit of the INTAC backbone. Structural analysis of DSS1–INTAC, both alone and in association with paused polymerase, demonstrates intimate interactions between DSS1 and the INTAC backbone. We identify tryptophan 39 of DSS1 as being critical for interacting with INTAC and find that its mutation disrupts DSS1’s interaction with INTAC, while maintaining DSS1’s interaction with the proteasome. This substitution not only impairs INTAC-dependent transcriptional regulation, but also reveals that INTAC is DSS1’s major chromatin-bound form. Together, our findings reveal a role for the versatile DSS1 protein in supporting the structure and regulatory functions of INTAC.
2025-07-09 | GSE297001 | GEO
Project description:We investigated the function of the Integrator Complex and PP2A during transcription.
2021-05-23 | GSE145379 | GEO
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
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 | GSE163803 | GEO
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 | GSE163802 | GEO
Project description:The phosphorylation and dephosphorylation of transcription machinery are essential for the precise control of gene expression. A non-canonical protein phosphatase 2A (PP2A) holoenzyme (denoted INTAC), in which the 14-subunit Integrator recruits RNA polymerase II (Pol II) and the PP2A core enzyme dephosphorylates the C-terminal repeat domain (CTD) of Pol II at Serine-5 and Serine-2.
2020-12-02 | GSE154093 | GEO
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
Project description:A PP2A-Integrator complex fine-tunes transcription by opposing CDK9
| PRJNA687654 | ENA