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G1 checkpoint is compromised in mouse ESCs due to functional uncoupling of p53-p21Waf1 signaling

Irina I Suvorova1,2, Bogdan B Grigorash1,2, Ilya A Chuykin3

  • 1a Institute of Cytology , Russian Academy of Sciences , St-Petersburg , Russia.

Cell Cycle (Georgetown, Tex.)
|December 5, 2015
PubMed

Insights

Mouse embryonic stem cells (mESCs) maintain pluripotency by preventing p21/Waf1 protein accumulation, which is regulated by epigenetic factors and proteasome degradation. Stabilizing p21/Waf1 triggers differentiation and restores the G1 checkpoint.

Area of Science:

  • Stem Cell Biology
  • Cell Cycle Regulation
  • DNA Damage Response

Background:

  • Mouse embryonic stem cells (mESCs) lack a G1 checkpoint, despite DNA damage activating ATM/ATR signaling.
  • Irradiation (IR) induces p53 and p21/Waf1 transcription but not p21/Waf1 protein accumulation in mESCs.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling p21/Waf1 protein levels in mESCs.
  • To determine the role of p21/Waf1 in maintaining ESC pluripotency and self-renewal.

Main Methods:

  • Treatment of mESCs with histone deacetylase inhibitors and proteasome inhibitors.
  • Analysis of p21/Waf1 transcription and protein levels following irradiation.
  • Assessment of cell cycle phase distribution, pluripotency gene expression (Oct4, Nanog), and differentiation markers (Sox17, Afp).
  • Nutlin treatment to stabilize p53.

Main Results:

  • p21/Waf1 expression is regulated epigenetically and via proteasome-dependent degradation in mESCs.
  • IR-induced p21/Waf1 protein accumulation occurs at later time points, correlating with G1 phase entry, reduced pluripotency gene expression, and differentiation.
  • Nutlin-induced p53 stabilization leads to p21/Waf1 accumulation, G1 checkpoint restoration, and differentiation onset.

Conclusions:

  • Functional p21/Waf1 is essential for maintaining mESC self-renewal and pluripotency.
  • The absence of p21/Waf1 protein accumulation allows mESCs to evade the G1 checkpoint and retain their pluripotent state.
Keywords:
ATM/ATR signaling; checkpoint control; DNA damage; HDAC inhibitors; p53-p21/Waf1 pathway; proteasomal degradation

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