Telomere dynamics in Fancg-deficient mouse and human cells.
A number of DNA repair proteins also play roles in telomere metabolism. To investigate whether the accelerated telomere shortening reported in Fanconi anemia (FA) hematopoietic cells relates to a direct role of the FA pathway in telomere maintenance, we have analyzed telomere dynamics in Fancg-deficient mouse and human cells. We show here that both hematopoietic (stem and differentiated bone marrow cells, B and T lymphocytes) and nonhematopoietic (germ cells, mouse embryonic fibroblasts [MEFs]) Fancg(-/-) mouse cells display normal telomere length, normal telomerase activity, and normal chromosome end-capping, even in the presence of extensive clastogen-induced cytogenetic instability (mitomycin C [MMC], gamma-radiation). In addition, telomerase-deficient MEFs with humanlike telomere length and decreased Fancg expression (G5 Terc(-/-)/Fancg shRNA3 MEFs) display normal telomere maintenance. Finally, early-passage primary fibroblasts from patients with FA of complementation group G as well as primary human cells with reduced FANCG expression (FANCG shRNA IMR90 cells) show no signs of telomere dysfunction. Our observations indicate that accelerated telomere shortening in patients with FA is not due to a role of FANCG at telomeres but instead may be secondary to the disease. These findings suggest that telomerase-based therapies could be useful prophylactic agents in FA aplastic anemia by preserving their telomere reserve in the context of the disease.
Molecular Oncology Program, Spanish National Cancer Centre, 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
Sonia
S
Franco
Henri J
HJ
van de Vrugt
Piedad
P
Fernández
Miguel
M
Aracil
Fre
F
Arwert
María A
MA
Blasco
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005199:Fanconi Anemia / Q000235:genetics; D052241:Fanconi Anemia Complementation Group G Protein; D005347:Fibroblasts / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000502:physiology; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C499909:FANCG protein, human; C499910:Fancg protein, mouse; D052241:Fanconi Anemia Complementation Group G Protein; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase