Functional interaction between DNA-PKcs and telomerase in telomere length maintenance
AUTOR(ES)
Espejel, Silvia
FONTE
Oxford University Press
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=137185Documentos Relacionados
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