Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases.
Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases.
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DOI：
10.1016/j.mad.2012.01.005
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发表时间：
2012-04
影响因子：
5.3
通讯作者：
Szczesny, Bartosz
中科院分区：
文献类型：
--
作者：
Hegde, Muralidhar L.;Mantha, Anil K.;Hazra, Tapas K.;Bhakat, Kishor K.;Mitra, Sankar;Szczesny, Bartosz
关键词：
活性氧（ROS）在呼吸过程中内源性或由遗传毒性物质外源性产生，诱导DNA中的碱基氧化和单链断裂（SSBs），并通过碱基切除/SSB修复（BER/SSBR）途径在细胞核和线粒体中进行修复。严格调控的BER/SSBR具有多个子通路，是高度复杂的，与复制和转录有关。修复启动DNA糖基酶（DGs）或ap内切酶（APE1）通常通过其共同作用域（CID）与下游蛋白稳定地相互作用来控制亚通路。具有无序结构的非保守CID通常位于其中一个末端，包括共价修饰和/或细胞器靶向序列。虽然DGs单独是可缺性的，但启动ssbr的APE1和多核苷酸激酶3 '磷酸酶（PNKP）是必不可少的。哺乳动物核基因组和线粒体基因组的BER/SSBR具有相同的早期酶。核和线粒体基因组中氧化损伤的积累与衰老和各种神经系统疾病有关。虽然BER/SSBR蛋白缺陷与遗传性神经退行性疾病有关，但我们最近的研究表明，过渡金属诱导的NEIL家族dg在散发性疾病中的抑制作用。本文综述了哺乳动物基因组氧化损伤修复及其与衰老和神经系统疾病联系的最新进展。
Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1), control the sub-pathway by stably interacting with downstream proteins usually via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini, includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3′ phosphatase (PNKP), are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.
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