RNA damage compartmentalization by DHX9 granules
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA902687 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Cell division ensures that both genetic information and non-genetic contents are inherited by daughter cells. Whereas considerable detail has been learned about the processing of intact or damaged DNA during the cell cycle (Branzei & Foiani, 2008; Klaasen et al., 2022),(Bakhoum & Cantley, 2018),(Hustedt & Durocher, 2016), how daughter cells deal with other forms of inherited damage is unknown. Here we identified a special kind of cytoplasmic granules responsible for the compartmentalisation of parental RNA damage. We found that ultraviolet (UV)-induced RNA, but not DNA, damage triggered assembly of this unique type of granules characterized by the presence of RNA helicase DHX9. By developing a novel methodology, FANCI, we discovered that DHX9 granules are enriched in damaged intron RNA and pre-mRNA-binding proteins, which is in contrast to other classical stress granules (SGs) that are composed of mature mRNA. Intron damage impeded proper splicing and intron decay, and induced generation of circRNA and dsRNA in the granules. Moreover, we showed that intron damage induced DHX9 granules assembled specifically in postmitotic daughter cells and triggered a cellular dsRNA immune response. Condensation with dsRNA is crucial for DHX9 localization to the granules and the modulation of dsRNA in these granules by DHX9 was crucial for daughter cell survival. Our observations revealed that DHX9 granules constitute a dedicated non-membrane-bound cytoplasmic compartment that protects daughter cells from parental damaged RNA.
2023-11-11 | GSE218180 | GEO
Project description:In our study, we valided DHX9 and NPM1 interact with KIMAT1, whereas DHX9 also interacts with HIF1A-As2. DHX9 is a highly conserved DEAD-box protein expressed in the nucleus and the cytoplasm, involved in many processes including transcriptional activation, miRNA biogenesis and tumor cell maintenance. NPM1 is predominantly localized in the nucleoplasm, where it associates with active RNA polymerase II and transcriptionally activates genes involved in cancer. We silenced DHX9 and NPM1 and performed RNA-seq to examine the dysregulated genes by DHX9 and NPM1.
2020-12-17 | GSE124626 | GEO
Project description:Chromatin compartmentalization regulates the response to DNA damage
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Project description:Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors where genomic instability contribute to pathology.
2024-02-01 | GSE244103 | GEO
Project description:The ATP-dependent DExH/D-box helicase DHX9 is a key participant in a number of gene regulatory steps, including transcriptional, translational, microRNA-mediated control, DNA replication, and maintenance of genomic stability. DHX9 has also been implicated in maintenance of the tumorigenic process and in drug response. Here, we report that inhibition of DHX9 expression is lethal to multiple human and mouse cancer cell lines. In contrast, using a novel conditional shDHX9 mouse model, we demonstrate that sustained and prolonged suppression of DHX9 is well tolerated at the organismal level. Our results demonstrate a robust tolerance for DHX9 knockdown in non-transformed cells and supports the targeting of DHX9 as an effective and specific chemotherapeutic approach. Comparison of gene expression in large intestine of mice with or without reduced expression of DHX9.
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Project description:Transposable elements increase genetic diversity thus making them an important part of evolution and gene regulation in all organisms that carry these sequences. Bulk of our nascent transcriptome is comprised of transposable elements that have the propensity to form strong secondary structures. It is essential to resolve such strong secondary structures to maintain normal cellular function. Here, we show that the major nuclear RNA helicase DHX9/RHA interacts and remodels embedded Alu retrotransposable elements in the human transcriptome and B1 retrotransposable elements in the mouse transcriptome. To understand the function of DHX9 we used FLASH (Fast cloning of RNA After some Sort of affinity purification for High-throughput sequencing) to identify the in-vivo targets of human DHX9.
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Project description:Transposable elements increase genetic diversity thus making them an important part of evolution and gene regulation in all organisms that carry these sequences. Bulk of our nascent transcriptome is comprised of transposable elements that have the propensity to form strong secondary structures. It is essential to resolve such strong secondary structures to maintain normal cellular function. Here, we show that the major nuclear RNA helicase DHX9/RHA interacts and remodels embedded Alu retrotransposable elements in the human transcriptome and B1 retrotransposable elements in the mouse transcriptome. To understand the function of DHX9 we used FLASH (Fast cloning of RNA After some Sort of affinity purification for High-throughput sequencing) to identify the in-vivo targets of human DHX9.
2017-03-28 | GSE89276 | GEO
Project description:Transposable elements increase genetic diversity thus making them an important part of evolution and gene regulation in all organisms that carry these sequences. Bulk of our nascent transcriptome is comprised of transposable elements that have the propensity to form strong secondary structures. It is essential to resolve such strong secondary structures to maintain normal cellular function. Here, we show that the major nuclear RNA helicase DHX9/RHA interacts and remodels embedded Alu retrotransposable elements in the human transcriptome and B1 retrotransposable elements in the mouse transcriptome. To understand the function of DHX9 we used FLASH (Fast cloning of RNA After some Sort of affinity purification for High-throughput sequencing) to identify the in-vivo targets of human DHX9.
2017-03-28 | GSE89751 | GEO
Project description:Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry”, has emerged as an effective strategy to convert immunologically “cold” tumors into “hot”. Through a curated CRISPR-based screen of RNA Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors where genomic instability contribute to pathology.
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