title: Mitotic DNA damage targets the Aurora A/TPX2 complex.
abstract: We have previously shown that the DNA damage-induced G2 arrest is contributed by inhibition of Aurora A (AurA) and that transduction of active AurA into arrested cells allows bypassing the block through reactivation of CDK1. In this study, we investigated the mechanism of DNA damage-induced AurA inhibition. We provide evidence that ionizing radiation (IR) administered in mitosis, a time when AurA protein and enzymatic activity reach peak levels, impairs interaction with the partner TPX2, leading to inactivation of the kinase through dephosphorylation of AurA T-loop residue, T288. We find that decreased AurA-TPX2 complex formation in response to irradiation results from reduced cellular levels of TPX2, an effect that is both contributed by increased APC/CDH1-dependent protein degradation and decreased translation of TPX2 mRNA.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Payal
authors.initials: P
authors.lastname: Bhatia
authors.forename: Mirco
authors.initials: M
authors.lastname: Menigatti
authors.forename: Michele
authors.initials: M
authors.lastname: Brocard
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Morley
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
mesh_terms: D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000528:radiation effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011839:Radiation, Ionizing
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C122167:TPX2 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases