title: The role of APC/C(Cdh1) in replication stress and origin of genomic instability.
abstract: It has been proposed that the APC/C(Cdh1) functions as a tumor suppressor by maintaining genomic stability. However, the exact nature of genomic instability following loss of Cdh1 is unclear. Using biochemistry and live cell imaging of single cells we found that Cdh1 knockdown (kd) leads to strong nuclear stabilization of the substrates cyclin A and B and deregulated kinetics of DNA replication. Restoration of the Cdh1-dependent G2 DNA damage checkpoint did not result in G2 arrest but blocked cells in prometaphase, suggesting that these cells enter mitosis despite incomplete replication. This results in DNA double-strand breaks, anaphase bridges, cytokinesis defects and tetraploidization. Tetraploid cells are the source of supernumerary centrosomes following Cdh1-kd, leading to multipolar mitosis or centrosome clustering, in turn resulting in merotelic attachment and lagging chromosomes. Whereas some of these events cause apoptosis during mitosis, surviving cells may accumulate chromosomal aberrations.
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Greil
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Krohs
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Schnerch
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Follo
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Felthaus
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Engelhardt
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center, Freiburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wäsch
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000235:genetics; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics*; D016193:G1 Phase / Q000235:genetics; D042822:Genomic Instability; D006801:Humans; D008938:Mitosis / Q000235:genetics; D011804:Quinolines / Q000494:pharmacology; D016196:S Phase / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D019926:Cyclin B; D011804:Quinolines; C512984:RO 3306; D013844:Thiazoles