Franco Sonia, van de Vrugt Henri J, Fernández Piedad, Aracil Miguel, Arwert Fre, Blasco María A
Molecular Oncology Program, Spanish National Cancer Centre, 3 Melchor Fernández Almagro, 28029 Madrid, Spain.
Blood. 2004 Dec 15;104(13):3927-35. doi: 10.1182/blood-2003-10-3626. Epub 2004 Aug 19.
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.
许多DNA修复蛋白也在端粒代谢中发挥作用。为了研究范可尼贫血（FA）造血细胞中报道的端粒加速缩短是否与FA通路在端粒维持中的直接作用有关，我们分析了Fancg缺陷的小鼠和人类细胞中的端粒动态变化。我们在此表明，造血细胞（造血干细胞和分化的骨髓细胞、B和T淋巴细胞）和非造血细胞（生殖细胞、小鼠胚胎成纤维细胞[MEF]）来源的Fancg(-/-)小鼠细胞均表现出正常的端粒长度、正常的端粒酶活性和正常的染色体末端封端，即使在存在广泛的致断裂剂诱导的细胞遗传不稳定的情况下（丝裂霉素C[MMC]、γ射线）。此外，具有类人端粒长度且Fancg表达降低的端粒酶缺陷型MEF（G5 Terc(-/-)/Fancg shRNA3 MEF）表现出正常的端粒维持。最后，来自互补组G型FA患者的早期传代原代成纤维细胞以及FANCG表达降低的原代人类细胞（FANCG shRNA IMR90细胞）未显示出端粒功能障碍的迹象。我们的观察结果表明，FA患者中端粒加速缩短并非由于FANCG在端粒上的作用，而是可能继发于该疾病。这些发现表明，基于端粒酶的疗法可能是FA再生障碍性贫血中有用的预防药物，通过在疾病背景下保留其端粒储备。
