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CRISPR screening reveals that RNA helicase DDX41 triggers ribosome biogenesis and cancer progression through R-loop-mediated RPL/RPS transcription

ABSTRACT: CRISPR screening reveals that RNA helicase DDX41 triggers ribosome biogenesis and cancer progression through R-loop-mediated RPL/RPS transcription

PROVIDER: PRJNA1188132 | ENA |

REPOSITORIES: ENA

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CRISPR screening reveals that RNA helicase DDX41 triggers ribosome biogenesis and cancer progression through R-loop-mediated RPL/RPS transcription

Project description:The RNA helicase DDX41 is a DEAD-box helicase that is well known as a virus sensor in dendritic cells and a tumor suppressor that is frequently mutated in myeloid neoplasms. However, the functions and relevance of DDX41 in solid tumors remain largely unexplored. In this study, through in vivo CRISPR screening, we demonstrated that DDX41 is highly expressed in various solid tumor types and promotes tumorigenicity in liver cancer. Mechanistically, DDX41 facilitates R-loop processing and accelerates the transcription of RPL/RPS genes, thereby promoting ribosome biogenesis and protein synthesis. Additionally, elevated DDX41 levels increase liver cancer cell sensitivity to protein synthesis inhibitors; treatment with homoharringtonine (HHT) significantly inhibits tumor growth in DDX41-overexpressing liver cancer models. Taken together, the results of this study highlight that DDX41 acts as an oncogene in liver cancer and suggest that protein synthesis inhibition may be a promising therapy for liver cancers with high DDX41 expression.

2024-12-23 | PXD059178 |

CRISPR screening reveals that RNA helicase DDX41 triggers ribosome biogenesis and cancer progression through R-loop-mediated RPL/RPS transcription

Project description:Our findings showed that high-expressed DDX41 translocates to the R-loop structure of RPL/RPS genes, accelerating their transcription and promoting ribosome biogenesis. Additionally, acetyltransferase KAT8 is required for H3K9ac modification of the DDX41 promoter, while NR2C1/NR2C2 are responsible for regulating DDX41 transcription.

2025-07-01 | GSE282326 | GEO

Inherited and somatic defects in DDX41 in myeloid neoplasms

Project description:Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-Box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases lead to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples.

2015-04-01 | E-GEOD-66668 | biostudies-arrayexpress

Role of RNA Helicase gene DDX41

Project description:Role of RNA Helicase gene DDX41

| PRJNA741462 | ENA

R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instabilityR-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability

Project description:Transcription can pose a threat to genomic stability through the formation of R-loops that obstruct the progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with a displaced non-template DNA strand. We developed RDProx to identify proteins that regulate R-loops in human cells. RDProx relies on the expression of the hybrid-binding domain (HBD) of Ribonuclease H1 (RNaseH1) fused to the ascorbate peroxidase (APEX2), which permits mapping of the R-loop proximal proteome using quantitative mass spectrometry. We associated R-loop regulation with different cellular proteins and identified a role of the tumor suppressor DEAD box protein 41 (DDX41) in opposing R-loop-dependent genomic instability. Depletion of DDX41 resulted in replication stress, double strand breaks and increased inflammatory signaling. Furthermore, DDX41 opposes accumulation of R-loops at gene promoters and its loss leads to upregulated expression of TGFβ and NOTCH signaling genes. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia (AML) in adulthood. We propose that accumulation of co-transcriptional R-loops, associated gene expression changes and inflammatory response contribute to the development of familial AML with mutated DDX41.

2021-11-25 | PXD024517 | Pride

Inherited and somatic defects in DDX41 in myeloid neoplasms

2015-04-01 | GSE66668 | GEO

Genome-wide maps of double strand breaks after siRNA knockdown of DDX41 in HCT116 cells

Project description:We report the first genome-wide mapping of fragility hotspots after siRNA-mediated knockdown of the DEAD-box helicase DDX41 in HCT116 cells using sBLISS. DDX41 defficient cells display elevated levels of genomic instability. sBLISS analysis revealed that hotspots for genomic instability in the absence of DDX41 are located around the transcription start site of transcribed genes.

2021-11-17 | GSE183147 | GEO

Comparative expression study regarding leukemia samples with DDX41 mutation

Project description:Genetic expression profiling (GEP) has previously proven useful in B-ALL for identifying signatures of oncogenes, with the recognition of novel subgroups, as well as with outcome. Therefore, we adopted GEP of bonemarrow samples of B-ALL with t(9;22) to uncover the contribution of DDX41 to leukemogenesis. The germline mutations of DDX41, also known as DEAD box RNA helicase 41, have been found in about 1.5% of myeloid neoplasms (MNs). Development of MDS/AML is relatively common in germline DDX41 mutations. However, a variety of hematological malignancies (HMs) have been reported. We report a novel case of bi-alleleic DDX41 mutations in B-cell lymphoblastic leukemia (B-ALL), with unusual location of DDX41 mutations. The gene expression profile (GEP) of Ph+ B-ALL with bi-alleleic DDX41 mutations showed heterogeneously transitional GEP and altered gene expression levels of genes involved in the process essential for red blood cells and myeloid cell differentiation were noted. We report that DDX41 mutations are unusual but can be an underlying event in Ph+B-ALL and screening DDX41 mutations can be also informative for patients awaiting for haploidentical stem cell transplantation and choosing the therapy.

2022-02-07 | GSE196107 | GEO

Gene expression profile of mouse hematopoieitic progenitor cell lines with inducible loss of Ddx41 expression

Project description:Germline mutations in the RNA Helicase gene DDX41 cause inherited predisposition to Myelodysplastic Syndrome and other myeloid blood malignancies. We characterized the effect of loss of one or both copies of the Ddx41 gene on the gene expression profile of immortalized hematopoietic progenitor cells.

2021-09-01 | GSE178891 | GEO

Nuclear RPSA triggers R-loop accumulation to induce cell death against RNA viral infection

Project description:While RNA viruses evade host immune responses by perturbing transcriptional and translational machinery, the host organism counteracts viral invasion through activation of regulated cell death pathways. However, the precise molecular mechanisms underlying host-initiated cell death activation in response to viral infection remain poorly characterized. By genome-wide screening, we identified ribosomal protein RPSA as a broad inducer of RNA virus replication-dependent cell death that confers antiviral protection. Rpsa conditional knockout mice exhibited heightened susceptibility to RNA viruses with attenuated cell death activation in infected tissues. Mechanistically, RNA virus infection triggers K29-linked polyubiquitination of RPSA, which strengthens its binding to the helicase domain of NAT10 and potently inhibits NAT10's helicase activity, thereby blocking R-loop resolution. The resulting R-loop accumulation drives DNA damage-mediated cell death execution. Our findings uncover a novel intranuclear "inside-out" R-loop-driven cell death pathway orchestrated by RPSA, providing fresh insights into virus-host interactions and identifying potential therapeutic targets for RNA viral infections.

2025-07-18 | GSE300291 | GEO

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