Functional interaction between DNA-PKcs and telomerase in telomere length maintenance.
DNA-PKcs is the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex that functions in the non-homologous end-joining of double-strand breaks, and it has been shown previously to have a role in telomere capping. In particular, DNA-PKcs deficiency leads to chromosome fusions involving telomeres produced by leading-strand synthesis. Here, by generating mice doubly deficient in DNA-PKcs and telomerase (Terc(-/-)/DNA-PKcs(-/-)), we demonstrate that DNA-PKcs also has a fundamental role in telomere length maintenance. In particular, Terc(-/-)/DNA-PKcs(-/-) mice displayed an accelerated rate of telomere shortening when compared with Terc(-/-) controls, suggesting a functional interaction between both activities in maintaining telomere length. In addition, we also provide direct demonstration that DNA-PKcs is essential for both end-to-end fusions and apoptosis triggered by critically short telomeres. Our data predict that, in telomerase-deficient cells, i.e. human somatic cells, DNA-PKcs abrogation may lead to a faster rate of telomere degradation and cell cycle arrest in the absence of increased apoptosis and/or fusion of telomere-exhausted chromosomes. These results suggest a critical role of DNA-PKcs in both cancer and aging.
Espejel
Silvia
S
Department of Immunology and Oncology, National Centre of Biotechnology, E-28049 Madrid, Spain.
Franco
Sonia
S
Sgura
Antonella
A
Gae
Darren
D
Bailey
Susan M
SM
Taccioli
Guillermo E
GE
Blasco
María A
MA
D000375:Aging / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy; D020134:Catalytic Domain; D002455:Cell Division; D002869:Chromosome Aberrations; D002875:Chromosomes / Q000648:ultrastructure; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000473:pathology; D017404:In Situ Hybridization, Fluorescence; D007248:Infertility, Male / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000502:physiology*; D013094:Spermatozoa / Q000473:pathology; D013154:Spleen / Q000166:cytology; D019098:Telomerase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016615:Telomere / Q000378:metabolism / Q000648:ultrastructure*; D013737:Testis / Q000473:pathology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C422952:telomerase RNA; D012313:RNA; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase