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EMBO J. 2010 May 5;29(9):1573-84. doi: 10.1038/emboj.2010.49. Epub 2010 Apr 20.

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

Author information

1
Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.

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.

PMID:
20407424
PMCID:
PMC2876953
DOI:
10.1038/emboj.2010.49
[Indexed for MEDLINE]
Free PMC Article

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