Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

DOI

10.15252/embj.201488947

Type

Journal article

Journal

EMBO J

Publication Date

03/02/2015

Volume

34

Pages

410 - 424

Keywords

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