DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress

Krenzlin, Harald; Demuth, Ilja; Salewsky, Bastian; Wessendorf, Petra; Weidele, Kathrin; Bürkle, Alexander; Digweed, Martin

DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress

Dateien

Krenzlin_217157.pdfGröße: 640.8 KBDownloads: 194

Datum

2012

Autor:innen

Krenzlin, Harald

Demuth, Ilja

Salewsky, Bastian

Wessendorf, Petra

Weidele, Kathrin

Bürkle, Alexander

Digweed, Martin

Open Access-Veröffentlichung

Open Access Gold

Sammlungen

Biologie

Publikationstyp

Zeitschriftenartikel

Publikationsstatus

Published

Erschienen in

PLoS Genetics. 2012, 8(3), e1002557. ISSN 1553-7390. eISSN 1553-7404. Available under: doi: 10.1371/journal.pgen.1002557

Zusammenfassung

Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Zitieren

ISO 690

KRENZLIN, Harald, Ilja DEMUTH, Bastian SALEWSKY, Petra WESSENDORF, Kathrin WEIDELE, Alexander BÜRKLE, Martin DIGWEED, 2012. DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress. In: PLoS Genetics. 2012, 8(3), e1002557. ISSN 1553-7390. eISSN 1553-7404. Available under: doi: 10.1371/journal.pgen.1002557

BibTex

@article{Krenzlin2012damag-21715,
  year={2012},
  doi={10.1371/journal.pgen.1002557},
  title={DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress},
  number={3},
  volume={8},
  issn={1553-7390},
  journal={PLoS Genetics},
  author={Krenzlin, Harald and Demuth, Ilja and Salewsky, Bastian and Wessendorf, Petra and Weidele, Kathrin and Bürkle, Alexander and Digweed, Martin},
  note={Article Number: e1002557}
}

RDF

<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/21715">
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21715/1/Krenzlin_217157.pdf"/>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-14T07:52:31Z</dc:date>
    <dc:creator>Salewsky, Bastian</dc:creator>
    <dcterms:title>DNA damage in Nijmegen Breakage Syndrome cells leads to PARP hyperactivation and increased oxidative stress</dcterms:title>
    <dcterms:abstract xml:lang="eng">Nijmegen Breakage Syndrome (NBS), an autosomal recessive genetic instability syndrome, is caused by hypomorphic mutation of the NBN gene, which codes for the protein nibrin. Nibrin is an integral member of the MRE11/RAD50/NBN (MRN) complex essential for processing DNA double-strand breaks. Cardinal features of NBS are immunodeficiency and an extremely high incidence of hematological malignancies. Recent studies in conditional null mutant mice have indicated disturbances in redox homeostasis due to impaired DSB processing. Clearly this could contribute to DNA damage, chromosomal instability, and cancer occurrence. Here we show, in the complete absence of nibrin in null mutant mouse cells, high levels of reactive oxygen species several hours after exposure to a mutagen. We show further that NBS patient cells, which unlike mouse null mutant cells have a truncated nibrin protein, also have high levels of reactive oxygen after DNA damage and that this increased oxidative stress is caused by depletion of NAD+ due to hyperactivation of the strand-break sensor, Poly(ADP-ribose) polymerase. Both hyperactivation of Poly(ADP-ribose) polymerase and increased ROS levels were reversed by use of a specific Poly(ADP-ribose) polymerase inhibitor. The extremely high incidence of malignancy among NBS patients is the result of the combination of a primary DSB repair deficiency with secondary oxidative DNA damage.</dcterms:abstract>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21715/1/Krenzlin_217157.pdf"/>
    <dc:contributor>Krenzlin, Harald</dc:contributor>
    <dc:creator>Weidele, Kathrin</dc:creator>
    <dc:contributor>Wessendorf, Petra</dc:contributor>
    <dc:creator>Digweed, Martin</dc:creator>
    <dc:contributor>Demuth, Ilja</dc:contributor>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:creator>Demuth, Ilja</dc:creator>
    <dc:language>eng</dc:language>
    <dc:contributor>Bürkle, Alexander</dc:contributor>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dc:contributor>Salewsky, Bastian</dc:contributor>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-14T07:52:31Z</dcterms:available>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/21715"/>
    <dc:creator>Bürkle, Alexander</dc:creator>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:contributor>Weidele, Kathrin</dc:contributor>
    <dc:contributor>Digweed, Martin</dc:contributor>
    <dc:rights>terms-of-use</dc:rights>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <dcterms:bibliographicCitation>PLoS Genetics ; 8 (2012), 3. - e1002557</dcterms:bibliographicCitation>
    <dcterms:issued>2012</dcterms:issued>
    <dc:creator>Wessendorf, Petra</dc:creator>
    <dc:creator>Krenzlin, Harald</dc:creator>
  </rdf:Description>
</rdf:RDF>

Universitätsbibliographie

Ja