title: The peptidyl prolyl isomerase cyclophilin A localizes at the centrosome and the midbody and is required for cytokinesis.
abstract: Failed cytokinesis leads to tetraploidy, which is an important intermediate preceding aneuploidy and the onset of tumorigenesis. The centrosome is required for the completion of cytokinesis through the transport of important components to the midbody; however, the identity of molecular components and the mechanism involved remains poorly understood. In this study, we report that the peptidyl prolyl isomerase cyclophilin A (cypA) is a centrosome protein that undergoes cell cycle-dependent relocation to the midzone and midbody during cytokinesis in Jurkat cells implicating a role during division. Depletion of cypA does not disrupt mitotic spindle formation or progression through anaphase; however, it leads to cytokinesis defects through an inability to resolve intercellular bridges, culminating in delayed or failed cytokinesis. Defective cytokinesis is also evident by an increased prevalence of midbody-arrested cells. Expression of wild-type cypA reverses the cytokinesis defect in knockout cells, whereas an isomerase mutant does not, indicating that the isomerisation activity of cypA is required for cytokinesis. In contrast, wild-type cypA and the isomerase mutant localize to the centrosome and midbody, suggesting that localization to these structures is independent of isomerase activity. Depletion of cypA also generates tetraploid cells and supernumerary centrosomes. Finally, colony formation in soft agar is impaired in cypA-knockout cells, suggesting that cypA confers clonogenic advantage on tumor cells. Collectively, this data reveals a novel role for cypA isomerase activity in the completion of cytokinesis and the maintenance of genome stability.
authors.affiliation: School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: John H
authors.initials: JH
authors.lastname: Bannon
authors.forename: Darragh S
authors.initials: DS
authors.lastname: O'Donovan
authors.forename: Susan M E
authors.initials: SM
authors.lastname: Kennelly
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Mc Gee
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism*; D021984:Cyclophilin A / Q000378:metabolism*; D048749:Cytokinesis / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D019169:Jurkat Cells; D011123:Polyploidy; D008941:Spindle Apparatus / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D021984:Cyclophilin A