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

Nele Hug, Stuart Aitken, Michaela Raab, H Armes, AR Mann, Ana Rio-machin, J Fitzgibbon, K Rouault-Pierre , Javier F. Caceres*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The DExD/H-box RNA helicase DHX34 is a Nonsense-mediated decay (NMD) factor that together with core NMD factors co-regulates 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 suggests that alterations in the levels and/or activity of DHX34 could contribute to human disease
Original languageEnglish
JournalRNA
Early online date29 Jun 2022
DOIs
Publication statusE-pub ahead of print - 29 Jun 2022

Keywords

  • DHX34
  • RNA helicase
  • NMD
  • pre-mRNA
  • splicing
  • RNA targets
  • seCLIP
  • AML

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