Residual Cdk1/2 activity after DNA damage promotes senescence

Aging Cell. 2017 Jun;16(3):575-584. doi: 10.1111/acel.12588. Epub 2017 Mar 26.

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.

Keywords: Cdk1; Cdk2; DNA damage response; G2 phase; cell cycle; checkpoint recovery; p21; senescence.

MeSH terms

  • Antigens, CD
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / genetics*
  • CDC2 Protein Kinase / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Size
  • Cell Survival / drug effects
  • Cellular Senescence / drug effects*
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / genetics*
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Etoposide / pharmacology*
  • G2 Phase Cell Cycle Checkpoints / drug effects*
  • Gene Expression Regulation
  • Humans
  • Osteoblasts / cytology
  • Osteoblasts / drug effects*
  • Osteoblasts / enzymology
  • Pteridines / pharmacology
  • Purines / pharmacology
  • Quinolines / pharmacology
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / enzymology
  • Signal Transduction
  • Single-Cell Analysis
  • Thiazoles / pharmacology

Substances

  • 4-(6-cyclohexylmethoxy-9H-purin-2-ylamino)-N,N-diethylbenzamide
  • Antigens, CD
  • BI 2536
  • CCNB1 protein, human
  • CDH1 protein, human
  • Cadherins
  • Cyclin B1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Pteridines
  • Purines
  • Quinolines
  • RO 3306
  • Thiazoles
  • Etoposide
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2