First Author | Espejel S | Year | 2002 |
Journal | EMBO J | Volume | 21 |
Issue | 22 | Pages | 6275-87 |
PubMed ID | 12426399 | Mgi Jnum | J:111398 |
Mgi Id | MGI:3653951 | Doi | 10.1093/emboj/cdf593 |
Citation | Espejel S, et al. (2002) Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. EMBO J 21(22):6275-87 |
abstractText | 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. |