Assessment of functional overlaps between human DNA repair pathways for 8-oxoguanine

评估 8-氧代鸟嘌呤的人类 DNA 修复途径之间的功能重叠

• 批准号: 449772894
• 负责人: Professor Dr. Andriy Khobta
• 金额: --
• 依托单位: Institut für Ernährungswissenschaften
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/449772894?language=en
• 关键词: Assessment; functional; overlaps; between; human

Generation of reactive oxidative species (ROS) and the resulting damage to DNA are unavoidable under physiological conditions and can be amplified by exogenous stressors, such as radiation, drugs and chemical compounds from diet and environmental sources. With an estimated generation rate of >1000 per day, 8-oxo-7,8-dihydroguanine (8-oxoG) is the most frequent oxidative DNA lesion in mammalian cells. 8-OxoG is pre-mutagenic due to the non-canonical (Hoogsteen type) base pairing with adenine during DNA replication. The resulting 8-oxoG:A mispairs, if persist into the next round of replication, produce characteristic G:C to T:A transversion mutations. A comprehensive defense pathway termed “GO system” protects from mutation by both eliminating 8-oxo-dGTP from the nucleotide pool and removing the 8-oxoG:C and 8-oxoG:A lesions from the genome. Base excision repair (BER) is the primary mechanism for repair of these DNA lesions in human cells; however, several lines of evidence suggested existence of auxiliary mechanisms in addition to the canonical BER. The proposed project is focused at identification of functional overlaps between BER and other DNA repair pathways in safeguarding human cells against the effects of 8-oxoG. We will address the existence of alternative mechanisms potentially relevant to the repair of 8-oxoG at three different levels: removal of pre-mutagenic 8-oxoG, prevention of toxicity at the post-excision step, and correction of the ultimately mutagenic 8-oxoG:A mispairs.

在生理条件下，反应性氧化物质（ROS）的产生和对DNA的损伤是不可避免的，并且可以通过外源性应激源（如辐射、药物和来自饮食和环境来源的化合物）来放大。8-氧代-7，8-二氢鸟嘌呤（8-oxoG）的生成速率估计为每天>1000个，是哺乳动物细胞中最常见的氧化性DNA损伤。8-由于在DNA复制过程中与腺嘌呤的非规范（Hoogsteen型）碱基配对，OxoG具有预致突变性。由此产生的8-oxoG：A错配，如果持续到下一轮复制，产生特征性的G：C到T：A颠换突变。称为“GO系统”的综合防御途径通过从核苷酸库中消除8-oxo-dGTP和从基因组中去除8-oxoG：C和8-oxoG：A损伤来保护免受突变。碱基切除修复（BER）是人类细胞中这些DNA损伤修复的主要机制;然而，一些证据表明，除了典型的BER之外，还存在辅助机制。该项目的重点是识别BER和其他DNA修复途径之间的功能重叠，以保护人类细胞免受8-oxoG的影响。我们将在三个不同的水平上解决可能与8-oxoG修复相关的替代机制的存在：去除预诱变的8-oxoG，在切除后步骤中预防毒性，以及纠正最终诱变的8-oxoG：A错配。