CDC7 inhibition drives an inflammatory response and a p53-dependent senescent-like state in breast epithelial cells

FEBS J. 2024 Jul;291(14):3147-3168. doi: 10.1111/febs.17127. Epub 2024 Mar 31.

Abstract

Drugs that block DNA replication prevent cell proliferation, which may result in anticancer activity. The latter is dependent on the drug's mode of action as well as on cell type-dependent responses to treatment. The inhibition of Cell division cycle 7-related protein kinase (CDC7), a key regulator of DNA replication, decreases the efficiency of origin firing and hampers the restarting of paused replication forks. Here, we show that upon prolonged CDC7 inhibition, breast-derived MCF10A cells progressively withdraw from the cell cycle and enter a reversible senescent-like state. This is characterised by the rewiring of the transcriptional programme with the induction of cytokine and chemokine expression and correlates with the accumulation of Cyclic GMP-AMP synthase (cGAS)-positive micronuclei. Importantly, cell fate depends on Cellular tumour antigen p53 (p53) function as cells no longer enter senescence but are funnelled into apoptosis upon p53 knockout. This work uncovers key features of the secondary response to CDC7 inhibitors, which could aid the development of these compounds as anticancer drugs.

Keywords: DNA replication; inflammation; kinase inhibitors; senescence.

MeSH terms

  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins* / antagonists & inhibitors
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Proliferation / drug effects
  • Cellular Senescence* / drug effects
  • DNA Replication / drug effects
  • Epithelial Cells* / drug effects
  • Epithelial Cells* / metabolism
  • Epithelial Cells* / pathology
  • Female
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Nucleotidyltransferases / antagonists & inhibitors
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism

Substances

  • Tumor Suppressor Protein p53
  • CDC7 protein, human
  • Cell Cycle Proteins
  • TP53 protein, human
  • Protein Serine-Threonine Kinases
  • Nucleotidyltransferases
  • cGAS protein, human