Selective mitochondrial DNA degradation following double-strand breaks

Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance o...

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Veröffentlicht in:PloS one Jg. 12; H. 4; S. e0176795
Hauptverfasser: Moretton, Amandine, Morel, Frédéric, Macao, Bertil, Lachaume, Philippe, Ishak, Layal, Lefebvre, Mathilde, Garreau-Balandier, Isabelle, Vernet, Patrick, Falkenberg, Maria, Farge, Géraldine
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Public Library of Science 28.04.2017
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ISSN:1932-6203, 1932-6203
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Abstract Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
AbstractList Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucle-ases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as reactive oxygen species, chemotherapeutic agents or ionizing radiations. MtDNA encodes for proteins involved in ATP production, and maintenance of genome integrity following DSBs is thus of crucial importance. However, the mechanisms involved in mtDNA maintenance after DSBs remain unknown. In this study, we investigated the consequences of the production of mtDNA DSBs using a human inducible cell system expressing the restriction enzyme PstI targeted to mitochondria. Using this system, we could not find any support for DSB repair of mtDNA. Instead we observed a loss of the damaged mtDNA molecules and a severe decrease in mtDNA content. We demonstrate that none of the known mitochondrial nucleases are involved in the mtDNA degradation and that the DNA loss is not due to autophagy, mitophagy or apoptosis. Our study suggests that a still uncharacterized pathway for the targeted degradation of damaged mtDNA in a mitophagy/autophagy-independent manner is present in mitochondria, and might provide the main mechanism used by the cells to deal with DSBs.
Audience Academic
Author Macao, Bertil
Farge, Géraldine
Ishak, Layal
Lachaume, Philippe
Falkenberg, Maria
Moretton, Amandine
Lefebvre, Mathilde
Morel, Frédéric
Vernet, Patrick
Garreau-Balandier, Isabelle
AuthorAffiliation 1 Université Clermont Auvergne, CNRS/IN2P3, Laboratoire de Physique de Clermont, BP 10448, F-63000 Clermont-Ferrand, France
2 Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30, Gothenburg, Sweden
Instituto de Biologia Molecular de Barcelona, SPAIN
AuthorAffiliation_xml – name: 1 Université Clermont Auvergne, CNRS/IN2P3, Laboratoire de Physique de Clermont, BP 10448, F-63000 Clermont-Ferrand, France
– name: 2 Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30, Gothenburg, Sweden
– name: Instituto de Biologia Molecular de Barcelona, SPAIN
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  fullname: Lachaume, Philippe
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  givenname: Layal
  surname: Ishak
  fullname: Ishak, Layal
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  givenname: Mathilde
  surname: Lefebvre
  fullname: Lefebvre, Mathilde
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  fullname: Farge, Géraldine
BackLink https://www.ncbi.nlm.nih.gov/pubmed/28453550$$D View this record in MEDLINE/PubMed
https://hal.science/hal-01693945$$DView record in HAL
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ContentType Journal Article
Copyright COPYRIGHT 2017 Public Library of Science
2017 Moretton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Distributed under a Creative Commons Attribution 4.0 International License
2017 Moretton et al 2017 Moretton et al
Copyright_xml – notice: COPYRIGHT 2017 Public Library of Science
– notice: 2017 Moretton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: Distributed under a Creative Commons Attribution 4.0 International License
– notice: 2017 Moretton et al 2017 Moretton et al
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IsDoiOpenAccess true
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Issue 4
Keywords Autophagic cell death
Nucleases
DNA replication
Mitochondria
Small interfering RNAs
Mitochondrial DNA
DNA repair
Apoptosis
Language English
License Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0
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Competing Interests: The authors have declared that no competing interests exist.
Conceptualization: FM PL PV MF GF.Data curation: GF.Formal analysis: AM.Funding acquisition: GF PV.Investigation: AM FM BM LI ML IGB GF.Methodology: AM GF.Project administration: GF.Resources: PV MF.Supervision: GF.Validation: GF FM.Visualization: AM GF.Writing – original draft: AM GF.Writing – review & editing: FM PV MF PL BM.
ORCID 0000-0003-1054-4274
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Snippet Mitochondrial DNA (mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as...
Mitochondrial DNA ( mtDNA) can undergo double-strand breaks (DSBs), caused by defective replication, or by various endogenous or exogenous sources, such as...
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SourceType Open Website
Open Access Repository
Aggregation Database
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Enrichment Source
StartPage e0176795
SubjectTerms Aging
Animal models
Apoptosis
Autophagy
Base excision repair
Biochemistry
Biochemistry, Molecular Biology
Biology and life sciences
Biomedical materials
Biotechnology
Blotting, Southern
Blotting, Western
Cell activation
Cell death
Cell lines
Cell proliferation
cells
Clinical Medicine
Clonal deletion
Copy number
Crystal structure
Cullin
Cyclin-dependent kinase
Cyclooxygenase 1 - genetics
damage
Degradation
Deoxyribonuclease
Deoxyribonucleic acid
Depletion
disease
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA Repair
DNA, Mitochondrial
DNA-directed DNA polymerase
Endonuclease
Endonucleases - metabolism
Enzymes
Exonucleases - metabolism
expression
Flow Cytometry
Gene expression
Gene therapy
Genetics
Genomes
Genomics
HEK293 Cells
Homology
Humans
inducible
Ionizing radiation
Kinetics
Klinisk medicin
Lesions
Life Sciences
Lung cancer
Maintenance
Mammals
Mathematical analysis
Millet
Mitochondria
Mitochondria - metabolism
Mitochondrial DNA
mtdna replication
Mutation
Neurodegenerative diseases
Nuclease
Nuclei
Nucleic acids
Organelles
Oxidative phosphorylation
Oxygen
Proteins
Quality control
Reaction kinetics
Reactive oxygen species
Real-Time Polymerase Chain Reaction
recombination
removal
repair
Replication
Sequence Analysis
targeted restriction-endonuclease
transcription factor-a
Transfection
Viability
Viruses
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Title Selective mitochondrial DNA degradation following double-strand breaks
URI https://www.ncbi.nlm.nih.gov/pubmed/28453550
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Volume 12
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