BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres

• Sophie Badie ^[2] ; Ana Rita Carlos ^[2] ; Cecilia Folio ^[2] ; Keiji Okamoto ^[1] ; Peter Bouwman ^[3] ; Jos Jonkers ^[3] ; Madalena Tarsounas ^[2]
  1. [1] Scripps Research Institute

     Scripps Research Institute

     Estados Unidos

     
  2. [2] 1 Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology Oxford, UK
  3. [3] 3 Division of Molecular Pathology and Cancer Systems Biology Centre, The Netherlands Cancer Institute Amsterdam, The Netherlands

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 34, Nº. 3, 2015, págs. 410-424
• Idioma: inglés
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• Resumen

  • 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 TRF2. 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 LIG4, or the alternative non-homologous end-joining (A-NHEJ), which relies on PARP1 and LIG3. Here, we show that the tumour suppressor BRCA1, together with its interacting partner CtIP, both acting in end resection, also promotes end-joining of uncapped telomeres. BRCA1 and CtIP 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, BRCA1 and CtIP act in the same pathway as LIG3 to promote joining of de-protected telomeres by A-NHEJ. Our work therefore ascribes novel roles for BRCA1 and CtIP 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.