Thrombopoietin-lncreased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Cell Stem Cell Année : 2013

Thrombopoietin-lncreased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage

Résumé

DNA double-strand breaks (DSBs) represent a serious threat for hematopoietic stem cells (HSCs). How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown. Thrombopoietin (TPO) and its receptor, Mpl, are critical factors supporting HSC self-renewal and expansion. Here, we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response. We show that DNA repair following gamma-irradiation (gamma-IR) or the action of topoisomerase-II inhibitors is defective in Mpl(-/-) and in wild-type mouse or human hematopoietic stem and progenitor cells treated in the absence of TPO. TPO stimulates DNA repair in vitro and in vivo by increasing DNA-PK-dependent nonhomologous end-joining efficiency. This ensures HSC chromosomal integrity and limits their long-term injury in response to IR. This shows that niche factors can modulate the HSC DSB repair machinery and opens new avenues for administration of TPO agonists for minimizing radiotherapy-induced HSC injury and mutagenesis.

Dates et versions

hal-01539615 , version 1 (15-06-2017)

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Berengere De Laval, Patrycja Pawlikowska, Laurence Petit-Cocault, Chrystele Bilhou-Nabera, Genevieve Aubin-Houzelstein, et al.. Thrombopoietin-lncreased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage. Cell Stem Cell, 2013, 12 (1), pp.37-48. ⟨10.1016/j.stem.2012.10.012⟩. ⟨hal-01539615⟩
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