BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres |
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| Authors: | Sophie Badie Ana Rita Carlos Cecilia Folio Keiji Okamoto Peter Bouwman Jos Jonkers Madalena Tarsounas |
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| Affiliation: | 1Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Oxford, UK;2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA;3Division of Molecular Pathology and Cancer Systems Biology Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands |
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| Abstract: | 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. |
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| Keywords: | alternative non-homologous end-joining BRCA1/CtIP telomere TRF2 |
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