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DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression

Alexis R Barr1, Samuel Cooper1,2, Frank S Heldt3

  • 1Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.

Nature Communications
|March 21, 2017
PubMed

Insights

The tumor suppressor p21, regulated by p53, maintains genomic stability by controlling cell cycle progression. It prevents premature S-phase entry, ensuring cells only divide after DNA repair.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The tumor suppressor p53 typically mediates cell cycle arrest following DNA damage via p21 expression.
  • The role of p21 in maintaining genomic stability without external DNA damage is not well understood.

Purpose of the Study:

  • To investigate the function of p21 in genomic stability during normal cell proliferation.
  • To elucidate the mechanisms regulating p21 levels and its impact on cell cycle progression.

Main Methods:

  • Live single-cell measurements of p21 protein levels in proliferating cultures.
  • Analysis of p53-dependent p21 accumulation during cell cycle phases.
  • Investigating the role of ubiquitin ligases CRL4Cdt2 and SCFSkp2 in p21 degradation.
  • Mathematical modeling of p21 regulation and cell cycle decisions.

Main Results:

  • Naturally occurring DNA damage during S-phase leads to p53-dependent p21 accumulation in G2 and G1 phases.
  • High p21 levels induce G1 arrest through CDK inhibition.
  • Lower p21 levels do not impede G1 progression, with degradation mediated by CRL4Cdt2 and SCFSkp2 before G1/S transition.
  • A bistable switch involving CRL4Cdt2 ensures low p21 levels, promoting irreversible S-phase entry and preventing premature exit upon DNA damage.

Conclusions:

  • p21 plays a crucial role in maintaining genomic stability by regulating the proliferation-quiescence decision.
  • The study reveals a novel mechanism where p21 levels are dynamically controlled to balance cell cycle progression and DNA damage response.
  • This regulation ensures cells commit to S-phase only after DNA repair, safeguarding genomic integrity.

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