title: Ku70 Serine 155 mediates Aurora B inhibition and activation of the DNA damage response.
abstract: The Ku heterodimer (Ku70/Ku80) is the central DNA binding component of the classical non-homologous end joining (NHEJ) pathway that repairs DNA double-stranded breaks (DSBs), serving as the scaffold for the formation of the NHEJ complex. Here we show that Ku70 is phosphorylated on Serine 155 in response to DNA damage. Expression of Ku70 bearing a S155 phosphomimetic substitution (Ku70 S155D) in Ku70-deficient mouse embryonic fibroblasts (MEFs) triggered cell cycle arrest at multiple checkpoints and altered expression of several cell cycle regulators in absence of DNA damage. Cells expressing Ku70 S155D exhibited a constitutive DNA damage response, including ATM activation, H2AX phosphorylation and 53BP1 foci formation. Ku70 S155D was found to interact with Aurora B and to have an inhibitory effect on Aurora B kinase activity. Lastly, we demonstrate that Ku and Aurora B interact following ionizing radiation treatment and that Aurora B inhibition in response to DNA damage is dependent upon Ku70 S155 phosphorylation. This uncovers a new pathway where Ku may relay signaling to Aurora B to enforce cell cycle arrest in response to DNA damage.
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Fell
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walden
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Hoffer
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Rogers
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Amelia S
authors.initials: AS
authors.lastname: Aitken
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Louisa M
authors.initials: LM
authors.lastname: Salemi
authors.affiliation: Robarts Research Institute and Department of Biochemistry, Schulich School of Medicine &Dentistry, The University of Western Ontario, London, Ontario N6A 5B7, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schild-Poulter
mesh_terms: D000818:Animals; D064107:Aurora Kinase B / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D011839:Radiation, Ionizing; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D012694:Serine; D064107:Aurora Kinase B; D000072200:Ku Autoantigen