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Mitochondrial DNA Stress Signalling Protects the Nuclear Genome

The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by...

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Autores principales: Wu, Zheng, Oeck, Sebastian, West, A. Phillip, Mangalhara, Kailash C., Sainz, Alva G., Newman, Laura E., Zhang, Xiao-Ou, Wu, Lizhen, Yan, Qin, Bosenberg, Marcus, Liu, Yanfeng, Sulkowski, Parker L., Tripple, Victoria, Kaech, Susan M., Glazer, Peter M., Shadel, Gerald S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213273/
https://www.ncbi.nlm.nih.gov/pubmed/32395698
http://dx.doi.org/10.1038/s42255-019-0150-8
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author Wu, Zheng
Oeck, Sebastian
West, A. Phillip
Mangalhara, Kailash C.
Sainz, Alva G.
Newman, Laura E.
Zhang, Xiao-Ou
Wu, Lizhen
Yan, Qin
Bosenberg, Marcus
Liu, Yanfeng
Sulkowski, Parker L.
Tripple, Victoria
Kaech, Susan M.
Glazer, Peter M.
Shadel, Gerald S.
author_facet Wu, Zheng
Oeck, Sebastian
West, A. Phillip
Mangalhara, Kailash C.
Sainz, Alva G.
Newman, Laura E.
Zhang, Xiao-Ou
Wu, Lizhen
Yan, Qin
Bosenberg, Marcus
Liu, Yanfeng
Sulkowski, Parker L.
Tripple, Victoria
Kaech, Susan M.
Glazer, Peter M.
Shadel, Gerald S.
author_sort Wu, Zheng
collection PubMed
description The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology(2,3). We showed previously that instability and cytoplasmic release of mtDNA activates the cGAS-STING-TBK1 pathway resulting in interferon stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs, that includes Parp9, remains activated by the unphosphorylated form of ISGF3 (U-ISGF3) that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS-STING-dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam(+/−) mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting mtDNA is a genotoxic stress sentinel.
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spelling pubmed-72132732020-06-01 Mitochondrial DNA Stress Signalling Protects the Nuclear Genome Wu, Zheng Oeck, Sebastian West, A. Phillip Mangalhara, Kailash C. Sainz, Alva G. Newman, Laura E. Zhang, Xiao-Ou Wu, Lizhen Yan, Qin Bosenberg, Marcus Liu, Yanfeng Sulkowski, Parker L. Tripple, Victoria Kaech, Susan M. Glazer, Peter M. Shadel, Gerald S. Nat Metab Article The mammalian genome comprises nuclear DNA (nDNA) derived from both parents and mitochondrial DNA (mtDNA) that is maternally inherited and encodes essential proteins required for oxidative phosphorylation. Thousands of copies of the circular mtDNA are present in most cell types that are packaged by TFAM into higher-order structures called nucleoids1. Mitochondria are also platforms for antiviral signalling2 and, due to their bacterial origin, mtDNA and other mitochondrial components trigger innate immune responses and inflammatory pathology(2,3). We showed previously that instability and cytoplasmic release of mtDNA activates the cGAS-STING-TBK1 pathway resulting in interferon stimulated gene (ISG) expression that promotes antiviral immunity4. Here, we find that persistent mtDNA stress is not associated with basally activated NF-κB signalling or interferon gene expression typical of an acute antiviral response. Instead, a specific subset of ISGs, that includes Parp9, remains activated by the unphosphorylated form of ISGF3 (U-ISGF3) that enhances nDNA damage and repair responses. In cultured primary fibroblasts and cancer cells, the chemotherapeutic drug doxorubicin causes mtDNA damage and release, which leads to cGAS-STING-dependent ISG activation. In addition, mtDNA stress in TFAM-deficient mouse melanoma cells produces tumours that are more resistant to doxorubicin in vivo. Finally, Tfam(+/−) mice exposed to ionizing radiation exhibit enhanced nDNA repair responses in spleen. Therefore, we propose that damage to and subsequent release of mtDNA elicits a protective signalling response that enhances nDNA repair in cells and tissues, suggesting mtDNA is a genotoxic stress sentinel. 2019-12-09 2019-12 /pmc/articles/PMC7213273/ /pubmed/32395698 http://dx.doi.org/10.1038/s42255-019-0150-8 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Wu, Zheng
Oeck, Sebastian
West, A. Phillip
Mangalhara, Kailash C.
Sainz, Alva G.
Newman, Laura E.
Zhang, Xiao-Ou
Wu, Lizhen
Yan, Qin
Bosenberg, Marcus
Liu, Yanfeng
Sulkowski, Parker L.
Tripple, Victoria
Kaech, Susan M.
Glazer, Peter M.
Shadel, Gerald S.
Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title_full Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title_fullStr Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title_full_unstemmed Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title_short Mitochondrial DNA Stress Signalling Protects the Nuclear Genome
title_sort mitochondrial dna stress signalling protects the nuclear genome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213273/
https://www.ncbi.nlm.nih.gov/pubmed/32395698
http://dx.doi.org/10.1038/s42255-019-0150-8
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