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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.

Original publication




Journal article



Publication Date





410 - 424


BRCA1/CtIP, TRF2, alternative non‐homologous end‐joining, telomere, Animals, Antigens, Nuclear, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, Carrier Proteins, Cell Cycle Proteins, DNA Damage, DNA End-Joining Repair, DNA Ligase ATP, DNA Ligases, DNA-Binding Proteins, HEK293 Cells, Humans, Ku Autoantigen, Mice, Mice, Knockout, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, Poly-ADP-Ribose Binding Proteins, Telomere, Xenopus Proteins