Work

Oncogenic DEAD-box ATPase DDX41 establishes transcript ensembles via CLK3-dependent and -independent mechanisms

Year: 2025

Type: article

Abstract: Post-transcriptional diversification of RNA transcripts mediated by complex processing machinery, including DEAD-box ATPases, establishes and maintains cellular phenotypes. For example, DDX41 controls RNA splicing, innate immune signaling, and genome stability. Although heterozygous DDX41 germline genetic variation occurs in familial myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DDX41 contributions to splicing globally, biological processes, and pathogenic mechanisms are incompletely defined. Using a genetic rescue system with Ddx41+/− myeloid progenitors, we established global wildtype DDX41 and pathogenic variant mechanisms. Differing from pathogenic variants of other RNA splicing regulators, DDX41 deficiency compromised multiple splicing steps. DDX41-regulated transcripts encoded factors controlling RNA splicing, including Cdc2-like kinase 3 (CLK3). DDX41 regulated Clk3 transcripts, and elevated CLK3 during myeloid differentiation. Loss-of-function analysis revealed DDX41-regulated splicing commonly, but not always, required CLK3. Thus, through a mechanism utilizing a splicing factor kinase that itself is DDX41-regulated, DDX41 establishes transcript ensembles in myeloid progenitors. Although DDX41 genetic variation occurs in myelodysplastic syndrome and acute myeloid leukemia, the pathogenic mechanisms remained unclear. Here, the authors found DDX41 regulates CLK3-dependent alternative splicing to establish transcript ensembles, while pathogenic variants limit the activity.

Source: Nature Communications

DOI: 10.1038/s41467-025-65195-z