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BRCA 1 and Ct IP promote alternative non‐homologous end‐joining at uncapped telomeres
Author(s) -
Badie Sophie,
Carlos Ana Rita,
Folio Cecilia,
Okamoto Keiji,
Bouwman Peter,
Jonkers Jos,
Tarsounas Madalena
Publication year - 2015
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 - 10.15252/embj.201488947
Subject(s) - telomere , gray (unit) , genome , library science , medicine , biology , genetics , dna , gene , computer science , nuclear medicine
Loss of telomere protection occurs during physiological cell senescence and ageing, due to attrition of telomeric repeats and insufficient retention of the telomere‐binding factor TRF 2. Subsequently formed telomere fusions trigger rampant genomic instability leading to cell death or tumorigenesis. Mechanistically, telomere fusions require either the classical non‐homologous end‐joining (C‐ NHEJ ) pathway dependent on Ku70/80 and LIG 4, or the alternative non‐homologous end‐joining (A‐ NHEJ ), which relies on PARP 1 and LIG 3. Here, we show that the tumour suppressor BRCA 1, together with its interacting partner Ct IP , both acting in end resection, also promotes end‐joining of uncapped telomeres. BRCA 1 and Ct IP do not function in the ATM ‐dependent telomere damage signalling, nor in telomere overhang removal, which are critical for telomere fusions by C‐ NHEJ . Instead, BRCA 1 and Ct IP act in the same pathway as LIG 3 to promote joining of de‐protected telomeres by A‐ NHEJ . Our work therefore ascribes novel roles for BRCA 1 and Ct IP in end‐processing and fusion reactions at uncapped telomeres, underlining the complexity of DNA repair pathways that act at chromosome ends lacking protective structures. Moreover, A‐ NHEJ provides a mechanism of previously unanticipated significance in telomere dysfunction‐induced genome instability.