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Cancer cells that survive checkpoint adaptation contain micronuclei that harbor damaged DNA

Cody W Lewis1, Roy M Golsteyn1

  • 1a Cancer Cell Laboratory, Department of Biological Sciences, University of Lethbridge , Lethbridge , AB , Canada.

Cell Cycle (Georgetown, Tex.)
|September 17, 2016
PubMed

Insights

Checkpoint adaptation in cancer cells leads to increased micronuclei formation, a process linked to DNA damage and genomic instability. Inhibiting this adaptation reduces micronuclei, suggesting a role in cancer progression.

Area of Science:

  • Cell Biology
  • Genetics
  • Cancer Research

Background:

  • Micronuclei in cancer cells are associated with genomic alterations and chromothripsis.
  • Checkpoint adaptation, defined as mitosis with damaged DNA, is a critical cellular process.
  • Understanding the link between checkpoint adaptation and micronuclei is crucial for cancer therapy.

Purpose of the Study:

  • To investigate the relationship between checkpoint adaptation and micronuclei formation in cancer cells.
  • To determine the effect of checkpoint modulation on cisplatin-induced micronuclei.
  • To explore the DNA replication status and DNA damage within micronuclei.

Main Methods:

  • Cytotoxicity assays of cisplatin on M059K glioma cells.
  • Immunofluorescence staining for histone γH2AX, DAPI, and lamin A/C to detect DNA damage and micronuclei.
  • Microscopy to quantify micronucleated cells and total micronuclei.
  • Treatment with checkpoint inhibitors and Cdk inhibitors.
  • Deoxy-bromo-uracil (BrdU) incorporation assays to assess DNA replication.

Main Results:

  • Cisplatin treatment induced significant DNA damage (γH2AX) and increased micronuclei formation in M059K cells.
  • Promoting mitosis with checkpoint inhibitors increased micronuclei, while Cdk inhibition reduced them.
  • Micronuclei exhibited asynchronous DNA replication and retained γH2AX staining, indicating ongoing DNA damage.
  • Normal WI-38 cells did not show increased micronuclei upon cisplatin treatment, lacking checkpoint adaptation.

Conclusions:

  • Checkpoint adaptation is a key driver of micronuclei production in cancer cells.
  • Micronuclei formation during checkpoint adaptation contributes to genomic instability and DNA damage.
  • Targeting checkpoint adaptation may offer a strategy to reduce genomic changes in cancer therapy.
Keywords:
M059K cellsWI-38 cellscheckpoint kinase 1cisplatincyclin dependent kinase 1

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