title: Hypersensitivity to DNA damage in antephase as a safeguard for genome stability.
abstract: Activation of the DNA-damage response can lead to the induction of an arrest at various stages in the cell cycle. These arrests are reversible in nature, unless the damage is too excessive. Here we find that checkpoint reversibility is lost in cells that are in very late G2, but not yet fully committed to enter mitosis (antephase). We show that antephase cells exit the cell cycle and enter senescence at levels of DNA damage that induce a reversible arrest in early G2. We show that checkpoint reversibility critically depends on the presence of the APC/C inhibitor Emi1, which is degraded just before mitosis. Importantly, ablation of the cell cycle withdrawal mechanism in antephase promotes cell division in the presence of broken chromosomes. Thus, our data uncover a novel, but irreversible, DNA-damage response in antephase that is required to prevent the propagation of DNA damage during cell division.
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: Femke M
authors: FM
authors: Feringa
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.|Hubrecht Institute, The Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht 3584CT, The Netherlands.
authors: Lenno
authors: L
authors: Krenning
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: André
authors: A
authors: Koch
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: Jeroen
authors: J
authors: van den Berg
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: Bram
authors: 0000-0003-1037-907X
authors: B
authors: van den Broek
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: Kees
authors: K
authors: Jalink
authors: Division of Cell Biology I and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
authors: René H
authors: RH
authors: Medema
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002877:Chromosomes, Human / Q000235:genetics; D004249:DNA Damage; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D059008:Time-Lapse Imaging
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome