Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice.
Non-homologous end joining (NHEJ) is the principal repair mechanism used by mammalian cells to cope with double-strand breaks (DSBs) that continually occur in the genome. One of the key components of the mammalian NHEJ machinery is the DNA-PK complex, formed by the Ku86/70 heterodimer and the DNA-PK catalytic subunit (DNA-PKcs). Here, we report on the detailed life-long follow-up of DNA-PKcs-defective mice. Apart from defining a role of DNA-PKcs in telomere length maintenance in the context of the ageing organism, we observed that DNA-PKcs-defective mice had a shorter life span and showed an earlier onset of ageing-related pathologies than the corresponding wild-type littermates. In addition, DNA-PKcs ablation was associated with a markedly higher incidence of T lymphomas and infections. In conclusion, these data link the dual role of DNA-PKcs in DNA repair and telomere length maintenance to organismal ageing and cancer.
Espejel
Silvia
S
Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain.
Martín
Marta
M
Klatt
Peter
P
Martín-Caballero
Juan
J
Flores
Juana M
JM
Blasco
María A
MA
D000375:Aging / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001835:Body Weight; D002453:Cell Cycle; D002875:Chromosomes / Q000378:metabolism / Q000648:ultrastructure; D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008017:Life Expectancy; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008540:Meiosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013131:Spine / Q000002:abnormalities; D016615:Telomere / Q000378:metabolism*; D013737:Testis / Q000166:cytology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases