Nucleic Acids Res:中科院北京基因组所赵永良研究组揭示线粒体基因

线粒体是真核生物细胞主要的能量代谢场所，其中呼吸链氧化磷酸化过程伴随有高水平的氧自由基(ROS)的产生。线粒体基因组缺乏组蛋白结合保护，所以容易受到ROS攻击而发生损伤，其突变的累积已证实与多种人类疾病(如神经退行性病变、糖尿病、心血管疾病和癌症等)的发生密切相关。有关核基因组DNA损伤修复分子机制已有大量的报道，而线粒体通过哪些关键基因或通路来修复氧化损伤以维持基因组的稳定性目前还不清楚。

着色性干皮症D(XPD)基因的编码产物是一种依赖于ATP的解旋酶，XPD在细胞核转录起始及核苷酸切除修复(NER)中发挥重要作用。近日，中国科学院北京基因组研究所精准基因组医学重点实验室赵永良研究组在线粒体氧化损伤修复研究中获得重要进展，该研究第一次证明XPD定位于线粒体内，并且参与线粒体基因组氧化性损伤修复过程。相关研究成果发表在核酸研究领域前沿期刊Nucleic Acids Research。

该研究发现，在氧化性损伤压力下，XPD在线粒体中分布显著升高，功能实验进一步证明，XPD缺陷导致线粒体基因组氧化损伤修复能力明显降低，表现为线粒体基因组突变率或缺失水平的明显升高。回补实验进一步证实了XPD蛋白解旋酶活性对于行使其功能起着关键的作用。另外，通过线粒体免疫沉淀及质谱分析证实了XPD蛋白与线粒体翻译延伸因子TUFM存在相互作用，而且，由XPD与TUFM形成的复合物在调控线粒体基因组氧化性损伤修复，以及维持线粒体基因组稳定性方面起着非常重要的作用。

原文链接:

XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage

原文摘要：

Xeroderma pigmentosum group D (XPD/ERCC2) encodes an ATP-dependent helicase that plays essential roles in both transcription and nucleotide excision repair of nuclear DNA, however, whether or not XPD exerts similar functions in mitochondria remains elusive. In this study, we provide the first evidence that XPD is localized in the inner membrane of mitochondria, and cells under oxidative stress showed an enhanced recruitment of XPD into mitochondrial compartment. Furthermore, mitochondrial reactive oxygen species production and levels of oxidative stress-induced mitochondrial DNA (mtDNA) common deletion were significantly elevated, whereas capacity for oxidative damage repair of mtDNA was markedly reduced in both XPD-suppressed human osteosarcoma (U2OS) cells and XPD-deficient human fibroblasts. Immunoprecipitation-mass spectrometry analysis was used to identify interacting factor(s) with XPD and TUFM, a mitochondrial Tu translation elongation factor was detected to be physically interacted with XPD. Similar to the findings in XPD-deficient cells, mitochondrial common deletion and oxidative damage repair capacity in U2OS cells were found to be significantly altered after TUFM knock-down. Our findings clearly demonstrate that XPD plays crucial role(s) in protecting mitochondrial genome stability by facilitating an efficient repair of oxidative DNA damage in mitochondria.

doi: 10.1093/nar/gkv472

作者：赵永良