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DNA double-strand break repair proteins in mitochondria of mammalian cells

哺乳动物细胞线粒体中的DNA双链断裂修复蛋白

基本信息

批准号：
17510057
负责人：
KOIKE MANABU
金额：
$ 2.3万
依托单位：
National Institute of Radiological Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

DNA double-strand break (DSB) is the most dangerous DNA damage. One DNA DSB can be sufficient to kill a cell, if it is not repaired. DNA DSB can be induced both exogenously, e.g., by ionizing radiation (IR), chemicals, and chemotherapeutics, and endogenously, e.g., in the process of recombination and replication or due to oxidative stresses. Two major pathways exist in mammalian cells for the repair of DNA DSB : nonhomologous DNA-end-joining (NHEJ) repair and homologous recombination (HR). The NHEJ repair process requires Ku70, Ku80, XRCC4, DNA Ligase IV, and DNA-PKcs. The HR repair process requires Rad51 and Rad52. The NHEJ repair process, which is responsible for repairing a major fraction of DNA DSB in somatic cells of all multicellular eukaryotes, is thought to begin with the binding of Ku. The mechanism of Ku-end recognition has been suggested by the recent resolution of the crystal structure of Ku: ring-like structure with high affinity DNA binding site around the central pore. Evidence for the importance of Ku in the NHEJ repair process has been reported. Cells genetically deficient in Ku are sensitive to ionizing radiation and other agents (e.g. etoposide) that generate DNA DSB. Mammals possess two cellular genomes, one in the nucleus and the other in the mitochondria. It is not well known whether in contrast to the nucleus, mammalian mitochondria are able to repair DSB, although it was reported that Ku80 is localized in mammalian mitochondria and functions in a DNA-end binding activity. In this study, I could not detect DSB-repair proteins, i.e., Ku70, Ku80, XRCC4 and Rad52 in mammal' s mitochondria examined.

DNA双链断裂(DSB)是最危险的DNA损伤。如果不进行修复，一个DNA DSB就足以杀死一个细胞。DNA DSB既可以由外源，如电离辐射(IR)、化学物质和化疗药物诱导，也可以内源性，如在重组和复制过程中或由于氧化应激而诱导。哺乳动物细胞中存在两条主要的DNA DSB修复途径：非同源DNA末端连接(NHEJ)修复和同源重组(HR)。NHEJ修复过程需要Ku70、Ku80、XRCC4、DNA连接酶IV和DNA-PKcs。人力资源维修流程需要RAD51和RAD52。NHEJ修复过程负责修复所有多细胞真核生物体细胞中DNA DSB的主要部分，被认为始于Ku的结合。最近对Ku晶体结构的解析揭示了Ku末端识别的机制：中心孔周围具有高亲和力DNA结合部位的环状结构。有证据表明Ku在NHEJ修复过程中的重要性。Ku基因缺陷的细胞对电离辐射和其他产生DNA DSB的试剂(如依托泊苷)非常敏感。哺乳动物有两个细胞基因组，一个在细胞核中，另一个在线粒体中。目前尚不清楚哺乳动物线粒体是否能够修复DSB，尽管已有报道Ku80定位于哺乳动物线粒体中，并具有DNA末端结合活性。在本研究中，我没有检测到哺乳动物S线粒体中的DSB修复蛋白，即Ku70、Ku80、XRCC4和Rad52。