title: Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1.
abstract: Loss of hematopoietic stem cell (HSC) function and increased risk of developing hematopoietic malignancies are severe and concerning complications of anticancer radiotherapy and chemotherapy. We have previously shown that thrombopoietin (TPO), a critical HSC regulator, ensures HSC chromosomal integrity and function in response to γ-irradiation by regulating their DNA-damage response. TPO directly affects the double-strand break (DSB) repair machinery through increased DNA-protein kinase (DNA-PK) phosphorylation and nonhomologous end-joining (NHEJ) repair efficiency and fidelity. This effect is not shared by other HSC growth factors, suggesting that TPO triggers a specific signal in HSCs facilitating DNA-PK activation upon DNA damage. The discovery of these unique signaling pathways will provide a means of enhancing TPO-desirable effects on HSCs and improving the safety of anticancer DNA agents. We show here that TPO specifically triggers Erk and nuclear factor κB (NF-κB) pathways in mouse hematopoietic stem and progenitor cells (HSPCs). Both of these pathways are required for a TPO-mediated increase in DSB repair. They cooperate to induce and activate the early stress-response gene, Iex-1 (ier3), upon DNA damage. Iex-1 forms a complex with pERK and the catalytic subunit of DNA-PK, which is necessary and sufficient to promote TPO-increased DNA-PK activation and NHEJ DSB repair in both mouse and human HSPCs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1016, Institut Cochin, Paris, France;
authors.forename: Bérengère
authors.initials: B
authors.lastname: de Laval
authors.forename: Patrycja
authors.initials: P
authors.lastname: Pawlikowska
authors.forename: Daniela
authors.initials: D
authors.lastname: Barbieri
authors.forename: Corinne
authors.initials: C
authors.lastname: Besnard-Guerin
authors.forename: Alba
authors.initials: A
authors.lastname: Cico
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Murielle
authors.initials: M
authors.lastname: Gaudry
authors.forename: Véronique
authors.initials: V
authors.lastname: Baud
authors.forename: Françoise
authors.initials: F
authors.lastname: Porteu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D020134:Catalytic Domain; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013926:Thrombopoietin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D016328:NF-kappa B; D013926:Thrombopoietin; D048049:Extracellular Signal-Regulated MAP Kinases