4.7 Article

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

Journal

CELL STEM CELL
Volume 12, Issue 1, Pages 37-48

Publisher

CELL PRESS
DOI: 10.1016/j.stem.2012.10.012

Keywords

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Funding

  1. INSERM
  2. Agence Nationale pour la Recherche [ANR-08-BLAN-0332]
  3. Ligue Contre le Cancer [RS12/75-67]
  4. DIM STEM-Pole
  5. Ministere de l'Enseignement Superieur et de la Recherche
  6. Fondation ARC
  7. Agence Nationale de la Recherche (ANR) [ANR-08-BLAN-0332] Funding Source: Agence Nationale de la Recherche (ANR)

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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.

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