TRF2/RAP1 and DNA-PK mediate a double protection against joining at telomeric ends

Abstract : DNA-dependent protein kinase (DNA-PK) is a double-strand breaks repair complex, the subunits of which (KU and DNA-PKcs) are paradoxically present at mammalian telomeres. Telomere fusion has been reported in cells lacking these proteins, raising two questions: how is DNA-PK prevented from initiating classical ligase IV (LIG4)-dependent non-homologous end-joining (C-NHEJ) at telomeres and how is the backup end-joining (EJ) activity (B-NHEJ) that operates at telomeres under conditions of C-NHEJ deficiency controlled? To address these questions, we have investigated EJ using plasmid substrates bearing double-stranded telomeric tracks and human cell extracts with variable C-NHEJ or B-NHEJ activity. We found that (1) TRF2/RAP1 prevents C-NHEJ-mediated end fusion at the initial DNA-PK end binding and activation step and (2) DNA-PK counteracts a potent LIG4-independent EJ mechanism. Thus, telomeres are protected against EJ by a lock with two bolts. These results account for observations with mammalian models and underline the importance of alternative non-classical EJ pathways for telomere fusions in cells.
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https://hal-ens-lyon.archives-ouvertes.fr/ensl-00815188
Contributor : Agnès Ganivet <>
Submitted on : Thursday, April 18, 2013 - 12:09:45 PM
Last modification on : Tuesday, November 19, 2019 - 2:47:13 AM

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  • HAL Id : ensl-00815188, version 1
  • DOI : 10.1038

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Oriane Bombarde, Céline Boby, Dennis Gomez, Philippe Frit, Marie-Josèphe Giraud-Panis, et al.. TRF2/RAP1 and DNA-PK mediate a double protection against joining at telomeric ends. EMBO Journal, EMBO Press, 2010, 29, pp.1573 - 1584. ⟨10.1038⟩. ⟨ensl-00815188⟩

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