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DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest

Jinho Lee1, Jin Ah Kim, Valerie Barbier

  • 1Institut de Biologie Structurale J-P Ebel, F38027 Grenoble, France.

Molecular Biology of the Cell
|February 13, 2009
PubMed

Insights

p21 protein prevents cell cycle progression after DNA damage by down-regulating Emi1, leading to anaphase-promoting complex activation and stable G2 arrest. This reveals a new p21-dependent mechanism in the G2 DNA damage checkpoint.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Cell cycle progression is tightly regulated by proteins like Emi1 and p21(WAF1).
  • p21(WAF1) acts as a cyclin-dependent kinase (CDK) inhibitor, activated by DNA damage.
  • Emi1 is an anaphase-promoting complex (APC) inhibitor, crucial for mitosis to G1 transition.

Purpose of the Study:

  • To investigate the role of p21(WAF1) in G2-M phase checkpoint control after DNA damage.
  • To understand how p21(WAF1) prevents polyploidy following DNA damage.
  • To elucidate the mechanism by which p21(WAF1) influences Emi1 and APC activity.

Main Methods:

  • Analysis of p21(+/+) and p21(-/-) cells following DNA damage.
  • Utilizing siRNA to down-regulate Emi1 expression.
  • Assessing APC activity and degradation of mitotic proteins (cyclins A2, B1).

Main Results:

  • p21(+/+) cells arrest in G2 after DNA damage, while p21(-/-) cells progress into mitosis.
  • p21 down-regulates Emi1 in G2-arrested cells, promoting APC activation and mitotic protein degradation.
  • Emi1 down-regulation by p21 is essential for stable G2 arrest; its inhibition rescues mitosis in p21(-/-) cells.
  • APC inactivation can overcome G2 arrest in irradiated p21(+/+) cells.

Conclusions:

  • p21-dependent Emi1 down-regulation and subsequent APC activation are critical for stable G2 arrest after DNA damage.
  • This study demonstrates a novel role for Emi1 regulation in the G2 DNA damage checkpoint.
  • A new p21-dependent mechanism for maintaining G2 arrest post-DNA damage has been identified.

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