title: XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage.
abstract: 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.
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Fang
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhenfen
authors.initials: Z
authors.lastname: Chi
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China Hebei North University, Zhangjiakou 075000, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wei
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Mo
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Kaifeng
authors.initials: K
authors.lastname: Niu
authors.affiliation: REAC/TS, Oak Ridge Associated Universities, Oak Ridge Institute of Science and Engineering, Oak Ridge, TN 37830, USA.
authors.forename: Adayabalam S
authors.initials: AS
authors.lastname: Balajee
authors.affiliation: Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China nielh@big.ac.cn.
authors.forename: Linghu
authors.initials: L
authors.lastname: Nie
authors.affiliation: Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China zhaoyongliang@big.ac.cn.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D020868:Gene Silencing; D054629:Genome, Mitochondrial; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress; D010444:Peptide Elongation Factor Tu / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion; D051759:Xeroderma Pigmentosum Group D Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C091648:TUFM protein, human; D010444:Peptide Elongation Factor Tu; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human