title: The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency.
abstract: 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.
authors.affiliation: 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.
authors.forename: Erwin
authors.initials: E
authors.lastname: Reiling
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Martijn E T
authors.initials: ME
authors.lastname: Dollé
authors.affiliation: Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Sameh A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Moonsook
authors.initials: M
authors.lastname: Lee
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Bhawani
authors.initials: B
authors.lastname: Nagarajah
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Roodbergen
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: de With
authors.affiliation: Faculty of Veterinary Medicine, Department of Pathobiology, Utrecht University, Utrecht, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hoeijmakers
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, The Netherlands; Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics* / Q000502:physiology; D001835:Body Weight / Q000235:genetics; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000235:genetics*; D051747:DNA-Activated Protein Kinase / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005260:Female; D055786:Gene Knockout Techniques; D000072200:Ku Autoantigen; D008136:Longevity / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D010641:Phenotype
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen
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