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RNA-DNA hybrids formed in the absence of Senataxin drive non-coding RNA expression and protein aggregation in the nucleolus

ABSTRACT: RNA-DNA hybrids formed in the absence of Senataxin drive non-coding RNA expression and protein aggregation in the nucleolus

PROVIDER: PRJNA1004589 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25617950_1.fastq.gz	Fastqsanger.gz
	SRR25617950_2.fastq.gz	Fastqsanger.gz
	SRR25617951_1.fastq.gz	Fastqsanger.gz
	SRR25617951_2.fastq.gz	Fastqsanger.gz
	SRR25617952_1.fastq.gz	Fastqsanger.gz

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RNA-DNA hybrids formed in the absence of Senataxin drive non-coding RNA expression and protein aggregation in the nucleolus

Project description:Neurodegeneration in the human population is often associated with loss of protein homeostasis that is driven by accumulation of specific aggregated proteins. Here we investigate whether deficiency in Senataxin, an RNA-DNA helicase associated with cerebellar ataxia and ALS, induces destabilization of intrinsically disordered proteins as we previously found with Ataxia-telangiectasia (A-T) cells and tissue. We find that Senataxin loss does generate protein aggregates but, unlike in A-T, these are associated with the nucleolus and are independent of oxidative stress and PARP activity. Non-coding RNA expression from the intergenic spacer region of ribosomal DNA is induced in the absence of Senataxin and drives the association and aggregation of many proteins known to be prone to aggregation in neurodegenerative disease. Both non-coding RNAs and protein aggregates are eliminated by overexpression of RNaseH1, implicating RNA-DNA hybrids as the key driver of these outcomes. We find that hybrids are high in the absence of Senataxin at intergenic sites, not at annotated protein-coding genes; these include sites of Senataxin binding in the genome, ribosomal DNA, and peri-centromeric regions. These findings suggest that destabilization of the proteome is driven by Senataxin loss and that RNA-DNA hybrids and non-coding RNAs play a critical role in this process.

2024-05-06 | GSE240664 | GEO

Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination.

Project description:We present a molecular dissection of pause site-dependent transcriptional termination for mammalian RNA polymerase II (Pol II)-transcribed genes. We show that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein associated with AOA2/ALS4 neurodegenerative disorders, acts to resolve these R-loop structures and by so doing allows access of the 5'-3' exonuclease Xrn2 at 3' cleavage poly(A) sites. This affords 3' transcript degradation and consequent Pol II termination. In effect, R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are key steps in the termination process.

| S-EPMC3145960 | biostudies-literature

INTS6 controls DNA:RNA hybrids autoregulation at double-strand break through Senataxin

Project description:The fidelity of transcription is essential for genome stability, especially when DNA damage happens. However, how the transcription cycle is regulated remains unknown. Here, we found that INTS6 is a fundamental player, which recruits PP2A to double-strand breaks (DSBs) and functions together with senataxin (SETX). The in-depth insight of ChromeRNA-seq shows that INTS6 is not only involved in global transcription termination but also the de novo transcription termination. Therefore, INTS6 is a great target for future translational studies.

2024-10-18 | GSE246729 | GEO

Mapping nucleolus-associated chromatin interactions by nucleolus-Hi-C reveals repression network

Project description:Nucleolus plays a key role in organizing global nuclear structure and facilitating gene regulation, but the three dimensional information within the nucleolus associated chromatins are still unknown, so here we development the Nucleolus Hi-C (NHi-C) experimental technique, which combines the nucleolus isolation with Hi-C experiment, and study the interactions within and surrounding nucleolus in human cells with a high resolution. With NHi-C experiment, we report how the nucleolus-associated chromatin regions interact at genome scale, and how these interactions organize the repressive nucleus architecture.

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ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

Project description:ENTPD3 Marks Mature Stem Cell Derived Beta Cells Formed by Self-Aggregation in Vitro

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INTS6 controls DNA:RNA hybrids autoregulation at double-strand break through Senataxin

Project description:INTS6 controls DNA:RNA hybrids autoregulation at double-strand break through Senataxin

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Mapping of nucleolus-associated chromosomal domains during replicative senescence.

Project description:Nucleolus-associated DNA was isolated from cross-linked proliferating and senescent IMR90 human fibroblasts and hybridized against genomic (1) or non-nucleolar (2) DNA to map nucleolus-associated chromosomal domains.

2017-06-18 | GSE78043 | GEO

Senataxin associates with replication forks to protect fork integrity across RNAPII transcribed genes

Project description:Here we analysed the role of yeast Senataxin (Sen1) in coordinating replication with transcription and in protecting genome integrity. Senataxin is mutated in the two severe neurodegenerative diseases AOA2 and ALS4. We show that a fraction of Sen1/Senataxin DNA/RNA helicase associates with replication forks and protects the integrity of those fork encountering highly expressed RNAPII genes. sen1 mutants accumulate aberrant DNA structures and RNA-DNA hybrids while forks clash head-on with RNAPII transcription units and counteract recombinogenic events and accumulation of checkpoint signals. Nrd1, which acts togheter with Sen1 in trascription temination, is not recruited at replication forks. nrd1 mutants does not display replication defects, high genome instability and checkpoint activation observed in sen1 mutants The Sen1 function in replication can be therefore separable from its role in RNA processing. We propose a role for Sen1/Senataxin during chromosome replication in facilitating replisome progression across RNAPII transcribed genes thus preventing DNA-RNA hybrids accumulation when forks encounter nascent transcripts on the lagging strand template.

2012-11-09 | GSE39139 | GEO

Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations.

Project description:Ataxia with oculomotor apraxia 2 (AOA-2) and amyotrophic lateral sclerosis (ALS4) are neurological disorders caused by mutations in the gene encoding for senataxin (SETX), a putative RNA:DNA helicase involved in transcription and in the maintenance of genome integrity. Here, using ChIP followed by high throughput sequencing (ChIP-seq), we report that senataxin is recruited at DNA double-strand breaks (DSBs) when they occur in transcriptionally active loci. Genome-wide mapping unveiled that RNA:DNA hybrids accumulate on DSB-flanking chromatin but display a narrow, DSB-induced, depletion near DNA ends coinciding with senataxin binding. Although neither required for resection nor for timely repair of DSBs, senataxin was found to promote Rad51 recruitment, to minimize illegitimate rejoining of distant DNA ends and to sustain cell viability following DSB production in active genes. Our data suggest that senataxin functions at DSBs in order to limit translocations and ensure cell viability, providing new insights on AOA2/ALS4 neuropathies.

| S-EPMC5803260 | biostudies-literature

Senataxin associates with replication forks to protect fork integrity across RNAPII transcribed genes

2012-11-09 | E-GEOD-39139 | biostudies-arrayexpress