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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.

SUBMITTER: Liu J

PROVIDER: S-EPMC4477675 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Liu Jing J Fang Hongbo H Chi Zhenfen Z Wu Zan Z Wei Di D Mo Dongliang D Niu Kaifeng K Balajee Adayabalam S AS Hei Tom K TK Nie Linghu L Zhao Yongliang Y

Nucleic acids research 20150512 11

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 reacti ...[more]

PMID: 25969448

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Project description:Cancer therapy resistance, whether it is pre-existing, emerges after acquiring de novo mutations, or occurs through non-genetic adaptationwhether pre-existing or arising following the acquisition of de novo mutations and via non-genetic adaptation , is stillremains a clinical challenge. Multiple anticancer drugs are thought to cause cell death via increasing mitochondrial ROS which are a bioproduct of oxidative phosphorylation. However, when properly titrated, ROS can also promote cancer cell adaptation. In keeping line with this, upregulation of mitochondrial respiration coupled to high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. Translational fidelity in the mitochondria and in the cytosol is essential for cell fitness and thus oxidative damage to the ribosomes should be prevented at all costs. While mechanisms for recognizing and repairing such damage exist in the cytoplasm, the status within mitochondria remains unclear. By performing ascorbate peroxidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear encoded lncRNA ROSALIND as a interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and immunogenicity both in vitro and ex vivo in preclinical humanized cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

Dataset Information

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

Publications

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

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