Ddx41 inhibition of DNA damage signaling permits erythroid progenitor expansion in zebrafish
| Autor: | Joshua T. Weinreb, Varun Gupta, Rachel Weil, Teresa V. Bowman, Elianna Sharvit |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Cell cycle checkpoint
biology DNA damage Kinase Mutant Alternative splicing Cell Cycle Proteins Hematology Ataxia Telangiectasia Mutated Proteins biology.organism_classification Cell Cycle Gene Cell biology DEAD-box RNA Helicases 03 medical and health sciences 0302 clinical medicine Erythropoiesis Animals Zebrafish 030215 immunology DNA Damage Signal Transduction |
| Zdroj: | Haematologica. 107(3) |
| ISSN: | 1592-8721 |
| Popis: | 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. Mis-expression 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 Ataxiatelangiectasia mutated (ATM) and Ataxia-telangiectasia 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. |
| Databáze: | OpenAIRE |
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