PUBLICATION
Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish
- Authors
- Weinreb, J.T., Gupta, V., Sharvit, E., Weil, R., Bowman, T.V.
- ID
- ZDB-PUB-210326-7
- Date
- 2021
- Source
- Haematologica 107(3): 644-654 (Journal)
- Registered Authors
- Bowman, Teresa
- Keywords
- none
- Datasets
- GEO:GSE160979
- MeSH Terms
-
- Animals
- Ataxia Telangiectasia Mutated Proteins/genetics
- Ataxia Telangiectasia Mutated Proteins/metabolism
- Cell Cycle Proteins/genetics
- DEAD-box RNA Helicases/genetics
- DNA Damage*
- Erythropoiesis/genetics
- Humans
- Signal Transduction
- Zebrafish*/metabolism
- PubMed
- 33763998 Full text @ Haematologica
Citation
Weinreb, J.T., Gupta, V., Sharvit, E., Weil, R., Bowman, T.V. (2021) Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish. Haematologica. 107(3):644-654.
Abstract
DEAD-box Helicase 41 (DDX41) is a recently identified factor mutated in hematologic malignancies whose function in hematopoiesis is unknown. Using an in vivo model of Ddx41 deficiency, we unveiled a critical role for this helicase in regulating erythropoiesis. We demonstrated that loss of ddx41 leads to anemia caused by diminished proliferation and defective differentiation of erythroid progenitors. Misexpression and alternative splicing of cell cycle genes is rampant in ddx41 mutant erythroid progenitors. We delineated that the DNA damage response is activated in mutant cells resulting in an Ataxia-telangiectasia mutated (ATM) and Ataxiatelangiectasia and Rad3-related (ATR)-triggered cell cycle arrest. Inhibition of these kinases partially suppressed ddx41 mutant anemia. These findings establish a critical function for Ddx41 in promoting healthy erythropoiesis via protection from genomic stress and delineate a mechanistic framework to explore a role for ATM and ATR signaling in DDX41-mutant hematopoietic pathologies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping