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

Nele Hug, Stuart Aitken, Dasa Longman, Michaela Raab, Hannah Armes, Abigail R Mann, Ana Rio-Machin, Jude Fitzgibbon, Kevin Rouault-Pierre , Javier F. Caceres*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1224-1238
JournalRNA
Volume28
Issue number9
Early online date29 Jun 2022
DOIs
Publication statusPublished - Sept 2022

Keywords / Materials (for Non-textual outputs)

  • Alternative Splicing
  • Animals
  • Humans
  • Leukemia, Myeloid, Acute/genetics
  • Mammals/genetics
  • Myelodysplastic Syndromes/genetics
  • Nonsense Mediated mRNA Decay
  • RNA Helicases/genetics
  • RNA Precursors/genetics
  • RNA Splicing
  • RNA, Messenger/genetics

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