title: Residual Cdk1/2 activity after DNA damage promotes senescence.
abstract: In response to DNA damage, a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after DNA damage until terminal cell cycle exit. This low level of Cdk activity not only allows cell cycle progression, but also promotes cell cycle exit at a decision point in G2 phase. We find that residual Cdk1/2 activity is required for efficient p21 production, allowing for nuclear sequestration of Cyclin B1, subsequent APC/CCdh1-dependent degradation of mitotic inducers and induction of senescence. We suggest that the same activity that triggers mitosis in an unperturbed cell cycle enforces senescence in the presence of DNA damage, ensuring a robust response when most needed.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Müllers
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Silva Cascales
authors.affiliation: Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Kamila
authors.initials: K
authors.lastname: Burdova
authors.affiliation: Laboratory of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Macurek
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arne
authors.identifier: 0000-0002-0141-1579
authors.initials: A
authors.lastname: Lindqvist
mesh_terms: D015703:Antigens, CD; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D048429:Cell Size; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005047:Etoposide / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011621:Pteridines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015398:Signal Transduction; D059010:Single-Cell Analysis; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C506606:4-(6-cyclohexylmethoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide; D015703:Antigens, CD; C518477:BI 2536; C534699:CCNB1 protein, human; C513384:CDH1 protein, human; D015820:Cadherins; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011621:Pteridines; D011687:Purines; D011804:Quinolines; C512984:RO 3306; D013844:Thiazoles; D005047:Etoposide; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: Cdk1; Cdk2; DNA damage response; G2 phase; cell cycle; checkpoint recovery; p21; senescence