title: p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation.
abstract: Chromosome loss or gain is associated with a large number of solid cancers, providing genomic plasticity and thus adaptability to cancer cells. Numerical centrosome abnormalities arising from centrosome over-duplication or failed cytokinesis are a recognized cause of aneuploidy. In higher eukaryotic cells, the centrosome duplicates only once per cell cycle to ensure the formation of a bipolar mitotic spindle that orchestrates the balanced distribution of the sister chromatids to the respective daughter cells. Here we delineate the events that allow abnormal centrosome duplication, resulting in mitotic errors and incorrect chromosome segregation in cells with sustained cyclin-dependent kinase (CDK) activity. We have identified NPM1 as a substrate for CDK6 activated by the Kaposi's sarcoma herpesvirus (KSHV) D-type cyclin and shown that p53-driven apoptosis occurs downstream of NPM1 phosphorylation as a checkpoint mechanism that prevents accumulation of cells with supernumerary centrosomes. Our findings provide evidence that abnormal chromosome segregation in KSHV-infected cells is a direct consequence of NPM1 phosphorylation and predict that genomic instability is an inevitable consequence of latent KSHV infection.
authors.affiliation: Cancer Research UK, Centre for Cell and Molecular Biology, The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB London, UK. emanuela@icr.ac.uk
authors.forename: Maria Emanuela
authors.initials: ME
authors.lastname: Cuomo
authors.forename: Axel
authors.initials: A
authors.lastname: Knebel
authors.forename: Nick
authors.initials: N
authors.lastname: Morrice
authors.forename: Hugh
authors.initials: H
authors.lastname: Paterson
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
authors.forename: Sibylle
authors.initials: S
authors.lastname: Mittnacht
mesh_terms: D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002503:Centromere / Q000648:ultrastructure; D018385:Centrosome / Q000378:metabolism / Q000648:ultrastructure*; D006224:Cricetinae; D003412:Cricetulus; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D048749:Cytokinesis; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D000090243:Nucleophosmin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; D018844:Cyclin-Dependent Kinases