Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects
Copyright policy )Disruption of Runx1 and Runx3 Leads to Bone Marrow Failure and Leukemia Predisposition due to Transcriptional and DNA Repair Defects
The RUNX genes encode transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here, we show that Runx1;Runx3 double-knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder. These contradictory clinical manifestations are reminiscent of human inherited bone marrow failure syndromes such as Fanconi anemia (FA), caused by defective DNA repair. Indeed, Runx1;Runx3 DKO cells showed mitomycin C hypersensitivity, due to impairment of monoubiquitinated-FANCD2 recruitment to DNA damage foci, although FANCD2 monoubiquitination in the FA pathway was unaffected. RUNX1 and RUNX3 interact with FANCD2 independently of CBFβ, suggesting a nontranscriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes the development of leukemias and other cancers.
- Agency for Science, Technology and Research Singapore
- Biomedical Research Council Singapore
- National University of Singapore Singapore
- RIKEN Japan
- Nationl University of Singapore Singapore
Leukemia, DNA Repair, QH301-705.5, Fanconi Anemia Complementation Group D2 Protein, HCT116 Cells, Mice, Inbred C57BL, Mice, Core Binding Factor Alpha 3 Subunit, Fanconi Anemia, HEK293 Cells, Bone Marrow, Core Binding Factor Alpha 2 Subunit, Animals, Humans, Genetic Predisposition to Disease, Biology (General), Gene Deletion, HeLa Cells
Leukemia, DNA Repair, QH301-705.5, Fanconi Anemia Complementation Group D2 Protein, HCT116 Cells, Mice, Inbred C57BL, Mice, Core Binding Factor Alpha 3 Subunit, Fanconi Anemia, HEK293 Cells, Bone Marrow, Core Binding Factor Alpha 2 Subunit, Animals, Humans, Genetic Predisposition to Disease, Biology (General), Gene Deletion, HeLa Cells
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