Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
PLoS Genet. 2013;9(7):e1003639. doi: 10.1371/journal.pgen.1003639. Epub 2013 Jul 18.
Telomeres are chromosome end structures and are essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible to oxidative stress-induced damage. Oxidation may therefore have a severe impact on telomere integrity and function. A wide spectrum of oxidative pyrimidine-derivatives has been reported, including thymine glycol (Tg), that are primarily removed by a DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect of Nth1 deficiency on telomere integrity in mice. Nth1 null (Nth1(-/-) ) mouse tissues and primary MEFs harbor higher levels of Endonuclease III-sensitive DNA lesions at telomeric repeats, in comparison to a non-telomeric locus. Furthermore, oxidative DNA damage induced by acute exposure to an oxidant is repaired slowly at telomeres in Nth1(-/-) MEFs. Although telomere length is not affected in the hematopoietic tissues of Nth1(-/-) adult mice, telomeres suffer from attrition and increased recombination and DNA damage foci formation in Nth1(-/-) bone marrow cells that are stimulated ex vivo in the presence of 20% oxygen. Nth1 deficiency also enhances telomere fragility in mice. Lastly, in a telomerase null background, Nth1(-/-) bone marrow cells undergo severe telomere loss at some chromosome ends and cell apoptosis upon replicative stress. These results suggest that Nth1 plays an important role in telomere maintenance and base repair against oxidative stress-induced base modifications. The fact that telomerase deficiency can exacerbate telomere shortening in Nth1 deficient mouse cells supports that base excision repair cooperates with telomerase to maintain telomere integrity.
端粒是染色体末端结构，对维持基因组稳定性至关重要。高度重复的端粒序列似乎容易受到氧化应激诱导的损伤。因此，氧化可能对端粒完整性和功能产生严重影响。已经报道了广泛的氧化嘧啶衍生物，包括胸腺嘧啶二醇（Tg），主要由 DNA 糖苷酶内切核酸酶 III 样蛋白 1（Nth1）去除。在这里，我们研究了 Nth1 缺陷对小鼠端粒完整性的影响。与非端粒位点相比，Nth1 缺失（Nth1(-/-)）小鼠组织和原代 MEF 中端粒重复序列处的内切核酸酶 III 敏感 DNA 损伤水平更高。此外，在 Nth1(-/-) MEF 中，急性暴露于氧化剂诱导的氧化 DNA 损伤在端粒处修复缓慢。尽管 Nth1(-/-) 成年小鼠造血组织中端粒长度不受影响，但在 20%氧气存在下体外刺激时，Nth1(-/-) 骨髓细胞中端粒会受到损耗、增加重组和 DNA 损伤焦点形成。Nth1 缺失也会增加小鼠端粒的脆性。最后，在端粒酶缺失背景下，Nth1(-/-) 骨髓细胞在复制应激时某些染色体末端会经历严重的端粒丢失和细胞凋亡。这些结果表明，Nth1 在端粒维持和碱基修复中发挥重要作用，以对抗氧化应激诱导的碱基修饰。端粒酶缺陷会加剧 Nth1 缺陷小鼠细胞中端粒缩短的事实表明，碱基切除修复与端粒酶合作维持端粒完整性。
