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

Area of Science:

• Genetics
• Hematology
• Molecular Biology

Background:

• Germline DDX41 variants are the most common inherited cause of myeloid neoplasms (MNs).
• The precise role of DDX41 in MN pathogenesis remains largely unknown.
• DDX41's function in specific hematopoietic lineages requires elucidation.

Purpose of the Study:

• To investigate the role of DDX41 in erythropoiesis and its implications in myeloid neoplasms.
• To determine the molecular mechanisms by which DDX41 variants contribute to MN development.
• To explore the relationship between DDX41, G-quadruplexes, and genome stability.

Main Methods:

• Generation of Ddx41 knockout mouse models for erythropoiesis studies.
• Analysis of G-quadruplex (G4) formation and co-localization with DDX41.
• Assessment of genome instability, p53 activation, and cGAS-STING pathway involvement.
• Utilized human induced pluripotent stem cell (iPSC)-derived bone marrow organoids and patient data.

Main Results:

• DDX41 is essential for erythropoiesis but dispensable for other hematopoietic lineages.
• DDX41 deficiency leads to G-quadruplex accumulation, compromising erythroid genome stability.
• G4 accumulation triggers p53 upregulation and activates the cGAS-STING pathway, contributing to lethality.
• DDX41 acts as a G4 resolvase, and its function is impaired in MN-associated mutants.

Conclusions:

• DDX41 is a critical G4 resolvase required for maintaining erythroid genome stability.
• Impaired DDX41 function leads to G4 accumulation and activation of the cGAS-STING innate immune pathway.
• This study clarifies DDX41's role in erythropoiesis and provides insights into MN pathogenesis.