TY - JOUR
T1 - Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to dna damage
AU - De Laval, Bérengère
AU - Pawlikowska, Patrycja
AU - Petit-Cocault, Laurence
AU - Bilhou-Nabera, Chrystèle
AU - Aubin-Houzelstein, Geneviève
AU - Souyri, Michèle
AU - Pouzoulet, Frédéric
AU - Gaudry, Murielle
AU - Porteu, Françoise
N1 - Funding Information:
We thank R. Dyunga for technical assistance; the Cochin Animal Facility; B. Durel of the Cochin Imaging Facility for microscopy analysis; D. Clay (Hospital Paul Brousse, Villejuif, France) and the Immunobiology Platform of the Cochin Institute for cell-sorting assistance; Drs. P. Bertrand (UMR CNRS 217, CEA, Fontenay aux Roses, France) and V. Gorbunova (University of Rochester, NY, USA) for the gifts of the pCOH NHEJ substrate, pcDNA-HA-I-SceI, and peGFP-Pem1-Ad2 constructs, respectively; and Dr. P. Sujobert for helpful discussions. This work was supported by INSERM and by grants from Agence Nationale pour la Recherche (ANR-08-BLAN-0332) and Ligue Contre le Cancer (RS12/75-67). P.P. is a recipient of fellowships from DIM STEM-Pôle. B.d.L received fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche and from the Fondation ARC.
PY - 2013/1/3
Y1 - 2013/1/3
N2 - 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 γ-irradiation (γ-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.
AB - 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 γ-irradiation (γ-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.
UR - http://www.scopus.com/inward/record.url?scp=84872047504&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2012.10.012
DO - 10.1016/j.stem.2012.10.012
M3 - Article
C2 - 23246483
AN - SCOPUS:84872047504
SN - 1934-5909
VL - 12
SP - 37
EP - 48
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -