The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency.
| Title: | The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency. |
|---|---|
| Authors: | 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. |
| Source: | PloS one [PLoS One] 2014 Apr 16; Vol. 9 (4), pp. e93568. Date of Electronic Publication: 2014 Apr 16 (Print Publication: 2014). |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science |
| MeSH Terms: | Aging/*genetics ; Antigens, Nuclear/*genetics ; DNA End-Joining Repair/*genetics ; DNA-Activated Protein Kinase/*genetics ; DNA-Binding Proteins/*genetics ; Nuclear Proteins/*genetics; Antigens, Nuclear/physiology ; Body Weight/genetics ; DNA-Activated Protein Kinase/physiology ; DNA-Binding Proteins/physiology ; Longevity/genetics ; Nuclear Proteins/physiology ; Animals ; DNA Damage ; Female ; Gene Knockout Techniques ; Ku Autoantigen ; Male ; Mice, Inbred C57BL ; Phenotype |
| 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. |
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| Grant Information: | P01 AG017242 United States AG NIA NIH HHS; P01 AG17242 United States AG NIA NIH HHS |
| Substance Nomenclature: | 0 (Antigens, Nuclear); 0 (DNA-Binding Proteins); 0 (Nuclear Proteins); EC 2.7.11.1 (DNA-Activated Protein Kinase); EC 2.7.11.1 (Prkdc protein, mouse); EC 3.6.4.12 (Xrcc6 protein, mouse); EC 4.2.99.- (Ku Autoantigen) |
| Entry Date(s): | Date Created: 20140418 Date Completed: 20150114 Latest Revision: 20211021 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3989187 |
| DOI: | 10.1371/journal.pone.0093568 |
| PMID: | 24740260 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural