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UAP56/DDX39b is a major co-transcriptional RNA-DNA helicase that unwinds harmful R loops genome-wide

ABSTRACT: UAP56/DDX39b is a major co-transcriptional RNA-DNA helicase that unwinds harmful R loops genome-wide

PROVIDER: PRJNA525976 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11838587_1.fastq.gz	Fastqsanger.gz
	SRR11838587_2.fastq.gz	Fastqsanger.gz
	SRR11838588_1.fastq.gz	Fastqsanger.gz
	SRR11838588_2.fastq.gz	Fastqsanger.gz
	SRR11838589_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

UAP56/DDX39b is a major co-transcriptional RNA-DNA helicase that unwinds harmful R loops genome-wide

Project description:Non-scheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R loop accumulation. One mechanism relies on the conserved THO complex in association with co-transcriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R loop removal. We show that UAP56 depletion causes R loop accumulation, R loop-mediated genome instability and replication fork stalling. We demonstrate an RNA-DNA helicase activity in UAP56 and that its overexpression suppresses R loops and genome instability induced by depleting 5 different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA-DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful co-transcriptional RNA structures that otherwise would block transcription and replication.

2020-05-25 | GSE127979 | GEO

UAP56/DDX39B is a major cotranscriptional RNA-DNA helicase that unwinds harmful R loops genome-wide.

Project description:Nonscheduled R loops represent a major source of DNA damage and replication stress. Cells have different ways to prevent R-loop accumulation. One mechanism relies on the conserved THO complex in association with cotranscriptional RNA processing factors including the RNA-dependent ATPase UAP56/DDX39B and histone modifiers such as the SIN3 deacetylase in humans. We investigated the function of UAP56/DDX39B in R-loop removal. We show that UAP56 depletion causes R-loop accumulation, R-loop-mediated genome instability, and replication fork stalling. We demonstrate an RNA-DNA helicase activity in UAP56 and show that its overexpression suppresses R loops and genome instability induced by depleting five different unrelated factors. UAP56/DDX39B localizes to active chromatin and prevents the accumulation of RNA-DNA hybrids over the entire genome. We propose that, in addition to its RNA processing role, UAP56/DDX39B is a key helicase required to eliminate harmful cotranscriptional RNA structures that otherwise would block transcription and replication.

| S-EPMC7328515 | biostudies-literature

The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate

Project description:Autoimmune disease is caused by environmental and genetic factors. Genetic factors associated with increased susceptibility to multiple sclerosis (MS), an autoimmune disease of the central nervous system, have been identified, but their mechanisms of action are incompletely understood.(Briggs, 2019) We previously established that the association between MS risk and the interleukin-7 receptor-a gene (IL7R) is mediated by alternative splicing of IL7R transcripts.(Gregory et al., 2007) This splicing is regulated by the RNA helicase DEAD Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with IL7R in enhancing MS risk (Galarza-Munoz et al., 2017). Here we discover that DDX39B, which is also known by immunologists as BAT1 (Spies et al., 1989), impacts the expression of many genes likely to play roles in autoimmunity.(Allcock et al., 2001; Degli-Esposti et al., 1992) We show that DDX39B controls expression of Forkhead Box P3 (FOXP3), a master regulator of the development, maintenance and function of CD4+/CD25+ T regulatory cells(Georgiev et al., 2019; Josefowicz et al., 2012) and repressor of autoimmunity (Bennett et al., 2001; Brunkow et al., 2001; Chatila et al., 2000; Wildin et al., 2001). Splicing of FOXP3 introns, which belong to a new subclass of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels, making FOXP3 expression highly sensitive to the levels of this RNA helicase. Low DDX39B levels in primary human T regulatory cells lead to loss of regulatory gene expression and cytokine signatures and gain of effector ones. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as a critically important guardian of immune tolerance that can reduce autoimmune disease risk by regulating IL7R splicing and upregulating FOXP3.

2022-01-20 | GSE145773 | GEO

Unwinding the roles of DEAD-box RNA helicases DDX39A and DDX39B in alternative RNA splicing

Project description:Dead-box RNA helicases are crucial in mRNA processing, specifically in RNA splicing. Our previous work has shown that DDX39B is responsible for regulating the splicing of IL7R exon 6 and several FOXP3 introns, which rely on DDX39B's helicase and ATPase activities, respectively [this is not accurate since exon 6 also must require the ATPase activity, which is required for helicase activity]. In this study, we aimed to investigate whether DDX39A, a highly homologous paralog of DDX39B, plays a similar role in regulating alternative RNA splicing. We find that DDX39A and DDX39B have significant redundancy in their gene targets, however, DDX39A is incapable of complementing defective splicing of IL7R exon 6 when DDX39B is knockdown. Conversely, overexpressing DDX39A can rescue FOXP3 intron 11 splicing under DDX39B-depleted conditions. In this work we also confirm that introns containing C-rich/U-poor polypyrimidine tract are very sensitive to DDX39B levels. We also observed that cassette exons with C-rich/U-poor py tracts in upstream introns were also sensitive to DDX39B levels and were skipped more upon depletion of DDX39B, but not DDX39A. Among the introns retained more upon DDX39A and DDX39B depletion were DDX39A and DDX39B intron 6, which depend on DDX39A and DDX39B levels, respectively. Therefore, we identified an autoregulatory mechanism through which DDX39A and DDX39B control their respective expression. This study presents evidence that while DDX39A and DDX39B differentially impact certain RNA splicing events, they have many shared targets.

2024-05-29 | GSE253261 | GEO

The RNA helicase DDX39B regulates IL7R alternative splicing reducing the risk of Multiple Sclerosis

Project description:Purpose: The goal of this study is to investigate the role of DDX39B in RNA splicing Methods: RNA-Seq splicing analysis of HeLa cells with experimentally induced DDX39B expression knockdown

2017-03-28 | GSE94730 | GEO

Harmful R loops are prevented via different cell cycle specific mechanisms

Project description:R loops induce transcription-replication (T-R) conflicts, but recent reports have suggested that R-loops are caused by T-R conflicts. Identifying how R loops are generated is crucial to know how transcription compromise genome integrity. Genome-wide analyses of conditional yeast mutants reveal that transcription factors, such as the THO complex. prevents R loop formation in G1 and S-phase, whereas the Sen1 DNA-RNA helicase prevents them only in S-phase. Interestingly, damage accumulates asymmetrically downstream of the RF in sen1 cells but symmetrically in the hpr1 THO mutant. Our results unambiguously indicate that: R loops forms co-transcriptionally independently of DNA replication; THO is a general and cell-cycle independent safeguard against R loops, and Sen1, in contrast to previously believed, is an S-phase-specific R loop resolvase. These conclusions have important implications for the mechanism of R loop formation and the role of other factors reported to impact on R loop homeostasis

2021-07-22 | GSE159870 | GEO

Harmful R loops are prevented via different cell cycle specific mechanisms

Project description:Harmful R loops are prevented via different cell cycle specific mechanisms

| PRJNA670705 | ENA

The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate

Project description:The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate

| PRJNA608194 | ENA

Suppression of DDX39B sensitizes ovarian cancer cells to DNA-damaging chemotherapeutic agents via destabilizing BRCA1 mRNA

Project description:Multiple RNA processing events including transcription, mRNA splicing and export are delicately coordinated by the TREX complex. As one of the essential subunits, DDX39B couples the splicing and export machineries by recruiting ALYREF onto mRNA. In this study, we further explore the functions of DDX39B in handling damaged DNA, and unexpectedly find that DDX39B facilitates DNA repair by homologous recombination through upregulating BRCA1. Specifically, DDX39B binds to and stabilizes BRCA1 mRNA. DDX39B ensures ssDNA formation and RAD51 accumulation at DSB sites by maintaining BRCA1 levels. Without DDX39B being present, ovarian cancer cells exhibit hypersensitivity to DNA-damaging chemotherapeutic agents like platinum or PARPi. Moreover, DDX39B-deficient mice show embryonic lethality or developmental retardation, highly reminiscent of those lacking BRCA1. High DDX39B expression is correlated with worse survival in ovarian cancer patients. Thus, DDX39B suppression represents a rational approach for enhancing the efficacy of chemotherapy in BRCA1-proficient ovarian cancers.

2020-08-21 | GSE156543 | GEO

The RNA-Binding Protein DDX39B Promotes Colorectal Adenocarcinoma Progression by Stabilizing DCLK1

Project description:As an RNA-binding protein (RBP), DDX39B increased the stability of DCLK1-B mRNA, a variant highly expressed in colorectal cancer known to promote cancer stemness, thereby augmenting its protein expression. Notably, silencing of DCLK1-B effectively abrogated the pro-metastatic effects induced by DDX39B overexpression.

2025-06-22 | GSE296923 | GEO

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