title: 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.
authors.affiliation: Institut de Pharmacologie et de Biologie Structurale, Toulouse, France.
authors.forename: Oriane
authors.initials: O
authors.lastname: Bombarde
authors.forename: Céline
authors.initials: C
authors.lastname: Boby
authors.forename: Dennis
authors.initials: D
authors.lastname: Gomez
authors.forename: Philippe
authors.initials: P
authors.lastname: Frit
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Giraud-Panis
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.forename: Bernard
authors.initials: B
authors.lastname: Salles
authors.forename: Patrick
authors.initials: P
authors.lastname: Calsou
mesh_terms: D004247:DNA / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
chemical_list: C000607893:LIG4 protein, human; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA; D051747:DNA-Activated Protein Kinase; D011088:DNA Ligases; D000072481:DNA Ligase ATP
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