The role of DNA damage and repair at telomeres

端粒 DNA 损伤和修复的作用

• 批准号: 8736607
• 负责人: Yie Liu
• 金额: $ 36.16万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736607
• 关键词: Ablation; Affect; Aging; Base Excision Repairs; Cell Aging; Cell Death; Cells; Chromosomes; DNA; DNA Damage; DNA Repair; DNA Repair Disorder; DNA glycosylase; DNA lesion; DNA repair protein; Defect; Disease; Excision; Functional disorder; Future; Genetic; Genome Stability; Genomic Instability; Goals; Guanine; Guidelines; Human; Investigation; Laboratories; Lead; Length; Lesion; Mammalian Cell; Modification; Molecular; Mouse Strains; Mus; Oxidative Stress; Play; Premature aging syndrome; Proteins; Pyrimidine; Pyrimidines; Role; Saccharomycetales; Specificity; Telomerase; Telomere Capping; Telomere Maintenance; Tissues; Work; age related; base; mouse model; oxidative DNA damage; oxidative damage; repaired; response; telomere

We have investigated whether telomeres are prone to oxidative DNA damage. In comparison to non-telomeric DNA, telomeric DNA harbors more oxidative base lesions, which is likely due to inefficient DNA repair at telomeres. Oxidative stress may result in a variety of DNA damages. Oxidative DNA base lesions are primarily repaired by base excision repair (BER). The initial step in BER is removal of the damaged base by a DNA glycosylase. Mammalian cells express several DNA glycosylases with overlapping, yet distinct specificities for different oxidative DNA lesions. We have initiated an investigation into the molecular mechanisms through which oxidative base lesions and DNA glycosylase deficiency affect telomere length/function. Previously we have examined the impact of oxidative guanine base lesions at telomeres in budding yeast and mice. We also found that a key BER protein, Ogg1 DNA glycosylase is critical in oxidative guanine base repair. Because oxidative stress can also cause oxidative modifications at pyrimidine bases, we have investigated if oxidative pyrimidine damage could accumulate at telomeres. We employed a mouse model with a loss in the Nth1 DNA glycosylase that excises oxidized pyrimidines. Nth1 deficiency leads to an increase in oxidative pyrimidine lesions at telomeres in mouse tissues and primary cells, suggesting that Nth1 is critical in repairing oxidative pyrimidine damage in telomeric DNA in mammalian cells. Ablation of Nth1 function results in telomere attrition and telomere strand breaks that are dependent on an environmental oxidative exposure. These results suggest that Nth1 plays an important role in telomere base repair and telomere maintenance against oxidative stress-induced DNA damage. The work was recently publisehd in Plos Genetics. Our long term goal is to investigate the role of oxidative base damage and BER deficiency in telomere damage-induced cellular senescence and organismal aging, particularly using mouse strains that mimic humans with regard to telomere length and telomerase activity. The will serve as useful guidelines for future studies that employ human cells.

我们已经研究了端粒是否容易受到氧化DNA损伤。与非telomeric DNA相比，端粒DNA具有更多的氧化碱病变，这可能是由于端粒的DNA修复效率低下所致。氧化应激可能导致多种DNA损伤。氧化DNA碱病变主要通过碱基切除修复（BER）修复。 BER的第一步是通过DNA糖基化酶去除受损的碱。哺乳动物细胞表达几种DNA糖基化酶，具有重叠但不同的特异性，但对于不同的氧化DNA病变。我们已经开始研究分子机制，氧化碱病变和DNA糖基化酶缺乏会影响端粒长度/功能。以前，我们已经检查了氧化鸟嘌呤碱病变对萌芽酵母和小鼠的端粒的影响。我们还发现，OGG1 DNA糖基酶在氧化鸟嘌呤碱基修复中至关重要。由于氧化应激也会在嘧啶碱下引起氧化修饰，因此我们研究了氧化嘧啶损伤是否会在端粒处积累。我们采用了一种在NTH1 DNA糖基化酶中损失的小鼠模型，该模型可将氧化的嘧啶切除。 NTH1缺乏导致小鼠组织和原代细胞中端粒上氧化嘧啶病变的增加，这表明NTH1对于修复哺乳动物细胞中端粒DNA中氧化嘧啶损伤至关重要。 NTH1功能的消融导致端粒损耗和端粒链断裂，这些断裂取决于环境氧化暴露。这些结果表明，NTH1在端粒碱基修复和端粒维持中起着重要作用，可抵抗氧化应激诱导的DNA损伤。这项工作最近在PLOS遗传学领域出版。我们的长期目标是研究氧化碱基损伤和BER缺乏在端粒损伤引起的细胞衰老和有机体衰老中的作用，尤其是使用模仿人类在端粒长度和端粒酶活性方面的小鼠菌株。该将作为使用人类细胞的未来研究的有用指南。