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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204987 | GEO | 2022/08/24

REPOSITORIES: GEO

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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (CLIP-Seq)

Project description:To investigate binding of DHX34 protein to RNA, RNA IP was performed in HEK293T cells using the seCLIP protocol.

2022-08-24 | GSE204982 | GEO

A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq II)

Project description:To investigate the effect of DHX34 and UPF1 depletion on transcription and splicing, DHX34 and UPF1 were knocked down in K562 cells.

2022-08-24 | GSE204985 | GEO

A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq I)

Project description:To investigate the effect of DHX34 depletion on transcription and splicing, DHX34 was knocked down in HeLa cells.

2022-08-24 | GSE204983 | GEO

A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its function in hematopoietic differentiation.

Project description:The DExD/H-box RNA helicase DHX34 is a nonsense-mediated decay (NMD) factor that together with core NMD factors coregulates NMD targets in nematodes and in vertebrates. Here, we show that DHX34 is also associated with the human spliceosomal catalytic C complex. Mapping of DHX34 endogenous binding sites using cross-linking immunoprecipitation (CLIP) revealed that DHX34 is preferentially associated with pre-mRNAs and locates at exon-intron boundaries. Accordingly, we observed that DHX34 regulates a large number of alternative splicing (AS) events in mammalian cells in culture, establishing a dual role for DHX34 in both NMD and pre-mRNA splicing. We previously showed that germline DHX34 mutations associated to familial myelodysplasia (MDS)/acute myeloid leukemia (AML) predisposition abrogate its activity in NMD. Interestingly, we observe now that DHX34 regulates the splicing of pre-mRNAs that have been linked to AML/MDS predisposition. This is consistent with silencing experiments in hematopoietic stem/progenitor cells (HSPCs) showing that loss of DHX34 results in differentiation blockade of both erythroid and myeloid lineages, which is a hallmark of AML development. Altogether, these data unveil new cellular functions of DHX34 and suggest that alterations in the levels and/or activity of DHX34 could contribute to human disease.

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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS

Project description:A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS

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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (CLIP-Seq)

Project description:A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (CLIP-Seq)

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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq I)

Project description:A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq I)

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A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq II)

Project description:A dual role for the RNA helicase DHX34 in NMD and pre-mRNA splicing and its role in familial AML/MDS (RNA-Seq II)

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Recurrent SRSF2 mutations in MDS affect both splicing and NMD.

Project description:Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splicing alterations that affect important regulators of hematopoiesis. Several mRNA isoforms promoted by the various splicing factor mutants comprise a premature termination codon (PTC) and are therefore potential targets of nonsense-mediated mRNA decay (NMD). In light of the mechanistic relationship between splicing and NMD, we sought evidence for a specific role of mutant SRSF2 in NMD. We show that SRSF2 Pro95 hot spot mutations elicit enhanced mRNA decay, which is dependent on sequence-specific RNA binding and splicing. SRSF2 mutants enhance the deposition of exon junction complexes (EJCs) downstream from the PTC through RNA-mediated molecular interactions. This architecture then favors the association of key NMD factors to elicit mRNA decay. Gene-specific blocking of EJC deposition by antisense oligonucleotides circumvents aberrant NMD promoted by mutant SRSF2, restoring the expression of PTC-containing transcript. Our study uncovered critical effects of SRSF2 mutants in hematologic malignancies, reflecting the regulation at multiple levels of RNA metabolism, from splicing to decay.

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A dual role for BBP/ScSF1 in nuclear pre-mRNA retention and splicing.

Project description:The MSL5 gene, which codes for the splicing factor BBP/ScSF1, is essential in Saccharomyces cerevisiae, yet previous analyses failed to reveal a defect in assembly of (pre)-spliceosomes or in vitro splicing associated with its depletion. We generated 11 temperature-sensitive (ts) mutants and one cold-sensitive (cs) mutant in the corresponding gene and analyzed their phenotypes. While all mutants were blocked in the formation of commitment complex 2 (CC2) at non-permissive and permissive temperature, the ts mutants showed no defect in spliceosome formation and splicing in vitro. The cs mutant was defective in (pre)-spliceosome formation, but residual splicing activity could be detected. In vivo splicing of reporters carrying introns weakened by mutations in the 5' splice site and/or in the branchpoint region was affected in all mutants. Pre-mRNA leakage to the cytoplasm was strongly increased (up to 40-fold) in the mutants. A combination of ts mutants with a disruption of upf1, a gene involved in nonsense-mediated decay, resulted in a specific synthetic growth phenotype, suggesting that the essential function of SF1 in yeast could be related to the retention of pre-mRNA in the nucleus.

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