title: An ATM and ATR dependent pathway targeting centrosome dependent spindle assembly.
abstract: The DNA damage checkpoint prevents the onset of DNA replication and mitosis when cells are exposed to genotoxic stress. However, it is not clear how cells react to DNA damage, in particular to DNA double strand breaks (DSBs) once they are in mitosis. Using Xenopus laevis egg extract as model system we have uncovered an ATM and ATR dependent checkpoint that targets centrosome dependent spindle assembly in the presence of chromosome breaks. This pathway relies on the phosphorylation by ATM and ATR of a novel centrosomal protein CEP63. We showed that CEP63 is required for proper spindle assembly in Xenopus and chicken DT40 cells. Phosphorylation of CEP63 by ATM and ATR leads to its delocalization from centrosomes and impairs its ability to promote centrosome dependent spindle assembly. These findings further support links uncovered in other model systems between the DNA damage checkpoint and centrosome in maintaining genome stability.
authors.affiliation: Genome Stability Unit, London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brown
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D018385:Centrosome / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability; D008938:Mitosis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D008941:Spindle Apparatus / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C539485:Cep63 protein, Xenopus; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C576898:Atr protein, Xenopus; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases