OXIDATIVE DNA DAMAGE AND ITS PROCESSING
DNA氧化损伤及其处理
基本信息
- 批准号:6431453
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Summary of work: Living organisms are constantly exposed to oxidative stress from environmental agents and from endogenous metabolic processes. The resulting oxidative modifications occur in proteins, lipids and DNA. Since proteins and lipids are readily degraded and resyn-thesized, the most significant consequence of the oxidative stress is thought to be the DNA modifications, which can become permanent via the formation of mutations and other types of genomic instability. Many different DNA base changes have been seen following some form of oxidative stress, and these lesions are widely considered as instigators for the development of cancer and are also implicated in the process of aging. Several studies have documented that oxidative DNA lesions accumulate with aging, and it appears that the major site of this accumulation is mitochondrial DNA rather than nuclear DNA. The DNA repair mechanisms involved in the removal of oxidative DNA lesions are much more complex than previously considered. They involve base excision repair (BER) pathways and nucleotide excision repair (NER) pathways, and there is currently a great deal of interest in clarification of the pathways and their interactions. We have used a number of different approaches to explore the mechanism of the repair processes, and we are able to examine the repair of different types of lesions and to measure different steps of the repair processes. Furthermore, we can measure the DNA damage processing in the nuclear DNA and separately, in the mitochondrial DNA. We have established in vitro assays using nuclear extracts from cells to measure the process of base excision repair of oxidative DNA damage. The experiments show that there are two forms of Base excision repair distinguishable by the length of the newly synthesized bases in DNA. We have shown that DNA polymerase beta is in volved in both of these processes, and that it plays a critical role, possibly in interaction with FLAP endonuclease FEN-1. We have disclosed a number of other protein interaction between proteins involved in the Base excision repair pathway. We have reconstituted this process in vitro and are exploring both physical and functional protein interactions. This suggests that a major base excision repair complex exists which includes AP endonuclease, proliferating cell nuclear antigen (PCNA), polymerase (s), glycosylase(s) and others. We have also established an in vitro assay for measuring DNA repair in mitochondria. Here we also characterize the DNA repair patch size and find that in the mitochodria there is only repair of the short length patch size type. Contrary to widely held notions, mitochondria have efficient DNA repair of oxidative DNA damage and we are exploring the mechanisms. In a human disorder, Cockayne syndrome (CS), characterized by premature aging, there appear to be deficiencies in the repair of oxidative DNA damage in the nuclear DNA, and this may be the major underlying cause of the disease.
工作概述:生物体不断暴露于环境因素和内源性代谢过程的氧化应激。由此产生的氧化修饰发生在蛋白质、脂质和DNA中。由于蛋白质和脂质容易降解和再合成,氧化应激的最重要后果被认为是DNA修饰,其可以通过形成突变和其他类型的基因组不稳定性而变得永久。 在某种形式的氧化应激之后,已经看到许多不同的DNA碱基变化,这些病变被广泛认为是癌症发展的诱因,并且也与衰老过程有关。 一些研究已经证明,氧化DNA损伤随着衰老而积累,并且似乎这种积累的主要部位是线粒体DNA而不是核DNA。 DNA修复机制涉及去除氧化DNA损伤比以前认为的要复杂得多。 它们涉及碱基切除修复(BER)途径和核苷酸切除修复(NER)途径,目前有大量的兴趣在澄清的途径和它们的相互作用。 我们已经使用了许多不同的方法来探索修复过程的机制,我们能够检查不同类型病变的修复,并测量修复过程的不同步骤。 此外,我们可以测量核DNA中的DNA损伤过程,并分别测量线粒体DNA中的DNA损伤过程。 我们已经建立了使用细胞核提取物的体外试验,以测量氧化性DNA损伤的碱基切除修复过程。实验表明,根据DNA中新合成碱基的长度,碱基切除修复有两种形式。我们已经证明DNA聚合酶β参与了这两个过程,并且它起着关键作用,可能与FLAP内切核酸酶FEN-1相互作用。我们已经公开了参与碱基切除修复途径的蛋白质之间的许多其他蛋白质相互作用。 我们已经在体外重建了这一过程,并正在探索物理和功能性蛋白质相互作用。 这表明存在主要的碱基切除修复复合物,其包括AP核酸内切酶、增殖细胞核抗原(PCNA)、聚合酶、糖基化酶等。我们还建立了一种体外测定线粒体DNA修复的方法。在这里,我们还描述了DNA修复补丁的大小,并发现在线粒体中只有短长度补丁大小类型的修复。与广泛持有的观念相反,线粒体具有有效的DNA修复氧化DNA损伤的能力,我们正在探索其机制。 Cockayne综合征(CS)是一种以过早衰老为特征的人类疾病,其核DNA氧化损伤的修复能力不足,这可能是该疾病的主要潜在原因。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Vilhelm A Bohr其他文献
Vilhelm A Bohr的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Vilhelm A Bohr', 18)}}的其他基金
Mitochondrial DNA Repair Processes In Oxidative Stress And Aging
氧化应激和衰老中的线粒体 DNA 修复过程
- 批准号:
10471691 - 财政年份:
- 资助金额:
-- - 项目类别:
DNA damage and repair in old and young and in participants in the BLSA
老年人、年轻人以及 BLSA 参与者的 DNA 损伤和修复
- 批准号:
8552452 - 财政年份:
- 资助金额:
-- - 项目类别:
相似海外基金
DNA repair pathway coordination during damage processing
损伤处理过程中 DNA 修复途径的协调
- 批准号:
10748479 - 财政年份:2024
- 资助金额:
-- - 项目类别:
CAREER: Mechanisms and consequences of epigenome-recruited DNA repair systems in plants
职业:植物中表观基因组招募的 DNA 修复系统的机制和后果
- 批准号:
2338236 - 财政年份:2024
- 资助金额:
-- - 项目类别:
Continuing Grant
Elucidation of the molecular link between DNA repair and mitochondrial nucleic acid metabolism
阐明DNA修复和线粒体核酸代谢之间的分子联系
- 批准号:
23K07078 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (C)
Biochemistry of Eukaryotic Replication Fork and DNA Repair
真核复制叉的生物化学和 DNA 修复
- 批准号:
10550045 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Structural studies for understanding the mechanism of DNA repair in chromatin
了解染色质 DNA 修复机制的结构研究
- 批准号:
23H05475 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (S)
Multifaceted regulation of the DNA repair machinery and suppression of aberrant transcription by telomere proteins
DNA 修复机制的多方面调控和端粒蛋白异常转录的抑制
- 批准号:
2246561 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
A role of balanced sex hormone in DNA repair in human melanocytes
平衡性激素在人类黑素细胞 DNA 修复中的作用
- 批准号:
10666307 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Natural products inhibitors targeting homology-directed DNA repair for cancer therapy
针对癌症治疗的同源定向 DNA 修复的天然产物抑制剂
- 批准号:
10651048 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Modeling the Responsiveness of Sensitive Populations to Genotoxic Agents Using DNA Repair Inhibitors
使用 DNA 修复抑制剂模拟敏感人群对基因毒性药物的反应性
- 批准号:
10734425 - 财政年份:2023
- 资助金额:
-- - 项目类别: