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BRCA1 and CtIP are required for processing uncapped telomeres
Author(s) -
Tarsounas Madalena
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.462.2
Subject(s) - homologous recombination , genome instability , microbiology and biotechnology , telomere , rad50 , dna damage , biology , dna repair , effector , cell cycle checkpoint , non homologous end joining , dna , cancer research , genetics , cell cycle , dna binding protein , cell , transcription factor , gene
BRCA1 tumour suppressor is a large phosphoprotein with key roles in the surveillance of genome integrity. As an E3 ubiquitylation enzyme, BRCA1 transduces DNA damage signals to the effector checkpoint kinases to arrest cell cycle progression and engage the homologous recombination pathway of DNA repair. A target of BRCA1‐dependent ubiquitylation is CtIP, which stimulates the nucleolytic activity of the MRE11‐RAD50‐NBS1 complex in vitro. BRCA1 is thought to promote resection at DNA double‐strand breaks by activating CtIP, a process counteracted by 53BP1. Here, we demonstrate that both BRCA1 and CtIP are required for the processing of DNA ends generated by telomere uncapping. Loss of the telomeric factor TRF2 in mouse embryonic fibroblasts causes disassembly of end protective structures, leading to chromosome fusions. Conditional Brca1 deletion or CtIP inhibition partially abrogates telomeric fusions in cell cycle‐dependent manner. BRCA1 and CtIP activities are specifically required during the post‐replicative processing of uncapped telomeres. Thus, in addition to non‐homologous end‐joining, BRCA1‐mediated repair facilitates processing of dysfunctional telomeres leading to genome instability.