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TRF2/RAP1 and DNA–PK mediate a double protection against joining at telomeric ends
Author(s) -
Bombarde Oriane,
Boby Céline,
Gomez Dennis,
Frit Philippe,
GiraudPanis MarieJosèphe,
Gilson Eric,
Salles Bernard,
Calsou Patrick
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.49
Subject(s) - telomere , biology , dna ligase , dna , non homologous end joining , microbiology and biotechnology , dna damage , genetics
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.