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

Authors: Liu, Jing; Fang, Hongbo; Chi, Zhenfen; Wu, Zan; Wei, Di; Mo, Dongliang; Niu, Kaifeng; Balajee, Adayabalam S; Hei, Tom K; Nie, Linghu; Zhao, Yongliang

Published In Nucleic Acids Res, (2015 Jun 23)

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.

PubMed ID: 25969448 Exiting the NIEHS site

MeSH Terms: Cell Line, Tumor; DNA Damage*; DNA Repair; Gene Silencing; Genome, Mitochondrial*; HEK293 Cells; Humans; Mitochondria/metabolism; Mitochondrial Proteins/analysis; Mitochondrial Proteins/antagonists & inhibitors; Mitochondrial Proteins/isolation & purification; Mitochondrial Proteins/metabolism*; Mitochondrial Proteins/physiology; Oxidative Stress*; Peptide Elongation Factor Tu/physiology; Reactive Oxygen Species/metabolism; Sequence Deletion; Xeroderma Pigmentosum Group D Protein/analysis; Xeroderma Pigmentosum Group D Protein/antagonists & inhibitors; Xeroderma Pigmentosum Group D Protein/deficiency; Xeroderma Pigmentosum Group D Protein/metabolism*

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