Fibroblast growth factor type 2 signaling is critical for DNA repair in human keratinocyte stem cells.
Tissue stem cells must be endowed with superior maintenance and repair systems to ensure genomic stability over multiple generations, which would be less necessary in more differentiated cells. We previously reported that human keratinocyte stem cells were more resistant to ionizing radiation toxicity than their direct progeny, the keratinocyte progenitor cells. In the present study we addressed the mechanisms underlying this difference. Investigations of DNA repair showed that both single and double DNA strand breaks were repaired more rapidly and more efficiently in stem cells than in progenitors. As cell signaling is a key regulatory step in the management of DNA damage, a gene profiling study was performed. Data revealed that several genes of the fibroblast growth factor type 2 (FGF2) signaling pathway were induced by DNA damage in stem cells and not in progenitors. Furthermore, an increased content of the FGF2 protein was found in irradiated stem cells, both for the secreted and the cellular forms of the protein. To examine the role of endogenous FGF2 in DNA repair, stem cells were exposed to FGF2 pathway inhibitors. Blocking the FGF2 receptor (FGF receptor 1) or the kinase (Ras-mitogen-activated protein kinase 1) resulted in a inhibition of single and double DNA strand-break repair in the keratinocyte stem cells. Moreover, supplementing the progenitor cells with exogenous FGF2 activated their DNA repair. We propose that, apart from its well-known role as a strong mitogen and prosurvival factor, FGF2 helps to maintain genomic integrity in stem cells by activating stress-induced DNA repair.
Harfouche
Ghida
G
CEA, iRCM, Laboratory of Genomics and Radiobiology of Keratinopoiesis, Evry, France.
Vaigot
Pierre
P
Rachidi
Walid
W
Rigaud
Odile
O
Moratille
Sandra
S
Marie
Mélanie
M
Lemaitre
Gilles
G
Fortunel
Nicolas O
NO
Martin
Michèle T
MT
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D013997:Time Factors
D000911:Antibodies, Monoclonal; D002070:Butadienes; C468783:H2AX protein, human; D006657:Histones; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; C113580:U 0126; D016222:Fibroblast Growth Factor 2; D012694:Serine