title: BRCA1 and CtIP promote alternative non-homologous end-joining at uncapped telomeres.
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.
authors.affiliation: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Oxford, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Badie
authors.affiliation: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Oxford, UK.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Carlos
authors.affiliation: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Oxford, UK.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Folio
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Keiji
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Division of Molecular Pathology and Cancer Systems Biology Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.affiliation: Division of Molecular Pathology and Cancer Systems Biology Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Oxford, UK madalena.tarsounas@oncology.ox.ac.uk.
authors.forename: Madalena
authors.initials: M
authors.lastname: Tarsounas
mesh_terms: D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000502:physiology*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins
chemical_list: D034961:Antigens, Nuclear; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D000072481:DNA Ligase ATP; D011088:DNA Ligases; D004268:DNA-Binding Proteins; D000072200:Ku Autoantigen; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000075223:Poly-ADP-Ribose Binding Proteins; D029867:Xenopus Proteins; C501070:RBBP8 protein, mouse; C000607893:LIG4 protein, human; C499321:Parp1 protein, mouse; C576325:Atm protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human; C000618818:Lig3 protein, mouse
keywords: BRCA1/CtIP; TRF2; alternative non‐homologous end‐joining; telomere