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The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency.
Reiling, Erwin; Dollé, Martijn E T; Youssef, Sameh A; Lee, Moonsook; Nagarajah, Bhawani; Roodbergen, Marianne; de With, Piet; de Bruin, Alain; Hoeijmakers, Jan H; Vijg, Jan; van Steeg, Harry; Hasty, Paul.
Afiliación
  • Reiling E; National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands.
  • Dollé ME; National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
  • Youssef SA; Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, The Netherlands.
  • Lee M; Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
  • Nagarajah B; National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
  • Roodbergen M; National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
  • de With P; National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
  • de Bruin A; Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, The Netherlands.
  • Hoeijmakers JH; Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands.
  • Vijg J; Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
  • van Steeg H; National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Hasty P; Department of Molecular Medicine and Institute of Biotechnology, Barshop Institute for Longevity and Aging Studies, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
PLoS One ; 9(4): e93568, 2014.
Article en En | MEDLINE | ID: mdl-24740260
Ku80 and DNA-PKCS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While ku80-/- mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in dna-pkcs-/- mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated ku80-/-, dna-pkcs-/- and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver and spleen using a lacZ reporter. Our data confirm that inactivation of Ku80 and DNA-PKCS causes reduced lifespan and bodyweights, which is most severe in ku80-/- mice. All mutant mice exhibited a strong increase in lymphoma incidence as well as other aging-related pathology (skin epidermal and adnexal atrophy, trabacular bone reduction, kidney tubular anisokaryosis, and cortical and medullar atrophy) and severe lymphoid depletion. LacZ mutation frequency analysis did not show strong differences in mutation frequencies between knock out and wild type mice. The ku80-/- mice had the most severe phenotype and the Ku80-mutation was dominant over the DNA-PKCS-mutation. Presumably, the more severe degenerative effect of Ku80 inactivation on lifespan compared to DNA-PKCS inactivation is caused by additional functions of Ku80 or activity of free Ku70 since both Ku80 and DNA-PKCS are essential for NHEJ.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Envejecimiento / Proteínas Nucleares / Antígenos Nucleares / Proteínas de Unión al ADN / Proteína Quinasa Activada por ADN / Reparación del ADN por Unión de Extremidades Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Envejecimiento / Proteínas Nucleares / Antígenos Nucleares / Proteínas de Unión al ADN / Proteína Quinasa Activada por ADN / Reparación del ADN por Unión de Extremidades Límite: Animals Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2014 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos