INTS6 controls DNA:RNA hybrids autoregulation at double-strand break through Senataxin
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE246729 | GEO | 2024/10/18
REPOSITORIES: GEO
Similar Datasets
Project description:This study shows that Integrator complex subunit 6 (INTS6) associates with the trimeric SOSS1 (comprising INTS3, INIP, and hSSB1) to form a tetrameric SOSS1 complex following DNA damage. INTS6 binds to DNA:RNA hybrids and plays a crucial role in Protein Phosphatase 2 (PP2A) recruitment to DNA double-strand breaks (DSBs), facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-induced RNA transcripts and stabilizes DNA:RNA hybrids at DSB sites. INTS6 interacts with, and promotes the recruitment of Senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. These data demonstrate the significance of the SOSS1 complex in autoregulating DNA:RNA dynamics and the promotion of efficient DNA repair.
2025-05-06 | PXD048694 | Pride
Project description:INTS6 controls DNA:RNA hybrids autoregulation at double-strand break through Senataxin
| PRJNA1034504 | ENA
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE280010 | GEO
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE280011 | GEO
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE297203 | GEO
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE280013 | GEO
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE280012 | GEO
Project description:Senataxin (SETX) is recognized as a critical regulator of RNA Polymerase II (RNAPII) transcription and plays a pivotal role in maintaining genomic stability. Despite its importance, the direct in vivo functions of SETX remain inadequately characterized. Employing the degradation tag (dTAG) system for acute protein depletion, we demonstrate that SETX does not influence transcription termination but significantly enhances RNAPII elongation. Through in vitro reconstitution assays, we show that SETX actively drives RNAPII forward across complex transcriptional landscapes, akin to the way bacterial ribosomes mitigate transcriptional pauses. In vivo analyses further reveal an accumulation of pausing RNAPII at early transcription stages and a corresponding increase in R-loop formation at these sites following SETX depletion. These insights not only redefine our understanding of SETX's role in transcriptional regulation but also highlight its potential as a therapeutic target in disorders linked to transcriptional dysregulation.
2025-11-13 | GSE297204 | GEO
Project description:Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. Total RNA samples obtained from 1) an AOA2 patient and carrier fibroblast cell lines, 2) 2 biological replicates of haploinsufficient SETX fibroblast cell lines transfected with one of 4 different wild-type and mutant SETX constructs, 3) peripheral blood from 33 patients and carriers across 12 families, and 4) 2 tissues from 2 Setx knockout and 2 control mice were analyzed using expression microarray. This submission represents the microarray component of study.
2014-09-15 | E-GEOD-61320 | biostudies-arrayexpress
Project description:Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. Total RNA samples obtained from 1) an AOA2 patient and carrier fibroblast cell lines, 2) 2 biological replicates of haploinsufficient SETX fibroblast cell lines transfected with one of 4 different wild-type and mutant SETX constructs, 3) peripheral blood from 33 patients and carriers across 12 families, and 4) 2 tissues from 2 Setx knockout and 2 control mice were analyzed using expression microarray. This submission represents the microarray component of study.
2014-09-15 | E-GEOD-61324 | biostudies-arrayexpress