Terminal differentiation induction as DNA damage response in hematopoietic stem cells by GADD45A  Susanne Wingert, Michael A. Rieger  Experimental Hematology  Volume 44, Issue 7, Pages 561-566 (July 2016) DOI: 10.1016/j.exphem.2016.04.006 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Experimental Hematology 2016 44, 561-566DOI: (10. 1016/j. exphem. 2016 Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 1 DNA damage responses in murine hematopoietic stem and committed progenitor cells. Simplified scheme of the major cell fate decisions and functions in response to DNA damage-causing incidents. Quiescent HSCs employ the error-prone NHEJ pathway as a DNA repair mechanism, whereas activated HSCs and committed progenitors use high-fidelity HR. HSCs are specifically resistant to DNA damage-causing conditions, even at the expense of accumulating mutations. Proposed here as a stem cell-mediated DDR, they terminally differentiate and thereby lose their self-renewal capacity to be eradicated from the system. Committed progenitors arrest primarily in their cell cycle or undergo cell death on DNA damage. Experimental Hematology 2016 44, 561-566DOI: (10.1016/j.exphem.2016.04.006) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions

Figure 2 Proposed functions of GADD45A in the DDR of adult HSCs. In contrast to several other cellular systems, GADD45A is not involved in mediating cell cycle arrest, and its absence may lead to only mild changes in the survival of adult HSCs. The upregulation of GADD45A robustly induces and accelerates the differentiation process via the MAPK p38 pathway. Loss-of-GADD45A function studies establish the role of GADD45A in mediating DNA repair. Both fate controls may have important tumor-suppressive functions in HSCs. Experimental Hematology 2016 44, 561-566DOI: (10.1016/j.exphem.2016.04.006) Copyright © 2016 ISEH - International Society for Experimental Hematology Terms and Conditions