DDX41 dissolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Germline DDX41 variants are the most common cause of inherited predisposition to myeloid neoplasms (MNs).
• The precise functions of DDX41 in hematopoiesis and the mechanisms by which its mutations lead to MNs are not fully understood.

Purpose of the Study:

• To elucidate the role of DDX41 in hematopoiesis.
• To investigate how DDX41 variants contribute to the development of myeloid neoplasms.

Main Methods:

• Utilized stage-specific Cre models for erythropoiesis to study Ddx41 function.
• Analyzed DNA G-quadruplex (G4) formation, genome instability, and pathway activation (p53, cGAS-STING) in Ddx41 deficient cells.
• Validated findings using patient-derived data and human induced pluripotent stem cell (iPSC)-derived bone marrow organoids.

Main Results:

• DDX41 is essential for erythropoiesis but dispensable for other hematopoietic lineages.
• DDX41 deficiency leads to G-quadruplex accumulation, erythroid genome instability, ribosomal biogenesis defects, and p53 upregulation.
• DDX41 directly binds and dissolves G4 structures; this function is impaired in MN-associated mutants.
• The cGAS-STING pathway activation due to genome instability is detrimental, as cGAS deficiency rescues lethality in Ddx41 knockout mice.

Conclusions:

• DDX41 functions as a G-quadruplex dissolver, critical for maintaining erythroid genome stability.
• DDX41 suppresses the cGAS-STING pathway, highlighting a novel mechanism in the pathogenesis of MNs.
• Understanding DDX41's role in G4 resolution offers potential therapeutic targets for inherited myeloid neoplasms.