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Functional interaction between DNA‐PKcs and telomerase in telomere length maintenance

Silvia Espejel, Sonia Franco, Antonella Sgura, Darren Gae, Susan M. Bailey, Guillermo E. Taccioli, María A. Blasco

Author Affiliations

  1. Silvia Espejel1,
  2. Sonia Franco1,
  3. Antonella Sgura1,2,
  4. Darren Gae3,
  5. Susan M. Bailey4,
  6. Guillermo E. Taccioli3 and
  7. María A. Blasco*,1
  1. 1 Department of Immunology and Oncology, National Centre of Biotechnology, E‐28049, Madrid, Spain
  2. 2 Department of Biology, University of Rome ‘Roma Tre’, Via le Marconi 446, Rome, 00146, Italy
  3. 3 Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118‐2526
  4. 4 Department of Radiological Health Sciences, Colorado State University, Fort Collins, CO, 80523, USA
  1. *Corresponding author. E-mail: mblasco{at}cnb.uam.es
  1. S.Espejel, S.Franco and A.Sgura contributed equally to this work

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Abstract

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.

  • Received August 25, 2002.
  • Revision received September 18, 2002.
  • Accepted September 19, 2002.
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