XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer
XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer
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DOI：
10.1038/ng1633
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发表时间：
2005-10-01
期刊：
影响因子：
30.8
通讯作者：
Blasco, MA
中科院分区：
文献类型：
--
作者：
Muñoz, P;Blanco, R;Blasco, MA
TRF2是一种端粒结合蛋白，在端粒保护中发挥作用。我们培育出了在皮肤中过度表达TRF2的小鼠。这些小鼠的皮肤对光的反应表现严重，包括皮肤过早恶化、色素沉着和皮肤癌增加，这类似于人类的着色性干皮病综合征。这些小鼠的角质形成细胞对紫外线和DNA交联剂超敏。这些小鼠的皮肤细胞有显著的端粒缩短、端粒G链悬垂丢失和染色体不稳定性增加。这些小鼠的端粒丢失是由XPF介导的，XPF是一种结构特异性核酸酶，参与紫外线诱导的损伤修复，并在患有着色性干皮病的个体中发生突变。这些发现表明，TRF2在端粒功能和紫外线诱导的损伤修复之间提供了关键的联系，端粒修复的改变是基因组不稳定、癌症和衰老的基础。最后，我们发现一些人类皮肤肿瘤增加了TRF2的表达，进一步强调了TRF2在皮肤癌中的作用。
TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.