TRF2/RAP1 and DNA-PK Mediate a Double Protection Against Joining at Telomeric Ends

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2010 Apr 22

PMID 20407424

Citations 48

Authors

Oriane Bombarde

Celine Boby

Dennis Gomez

Philippe Frit

Marie-Josephe Giraud-Panis

Eric Gilson

Bernard Salles

Patrick Calsou

Affiliations

Soon will be listed here.

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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