Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells

Elife. 2018 Oct 16:7:e37868. doi: 10.7554/eLife.37868.


In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks. In this system, loss of p53 allowed mitogen-independent proliferation, not by suppressing apoptosis, but rather by restoring origin firing and reducing DNA breakage. Loss of G1/S control also caused DNA damage and activation of p53 in an in vivo retinoblastoma model. Moreover, in a teratoma model, loss of p53 reduced DNA breakage. Thus, loss of p53 may promote growth of incipient cancer cells by reducing replication-stress-induced DNA damage.

Keywords: DNA double strand breaks; G1/S phase checkpoint; cancer biology; human; mouse; origin firing; p53; replication stress; retinoblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • DNA Breaks, Double-Stranded
  • DNA Damage / genetics*
  • DNA Repair / genetics
  • DNA Replication / genetics*
  • Humans
  • Mice
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • S Phase / genetics
  • Teratoma / genetics
  • Teratoma / pathology
  • Tumor Suppressor Protein p53 / genetics*


  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Tumor Suppressor Protein p53