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Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain.

Helge M Magnussen1,2, Syed F Ahmed1, Gary J Sibbet1

  • 1Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.

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|May 1, 2020
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Summary
This summary is machine-generated.

Phosphorylation of MDM2 at Ser429 by ATM enhances its ubiquitin ligase activity, promoting MDM2 self-destruction and enabling p53 activation after DNA damage.

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Area of Science:

  • Molecular biology
  • Biochemistry
  • Cellular signaling

Background:

  • DNA damage response pathways are crucial for maintaining genomic stability.
  • MDM2 (mouse double minute 2 homolog) is a key E3 ubiquitin ligase that regulates the tumor suppressor p53.
  • ATM (ataxia-telangiectasia mutated) kinase plays a central role in the DNA damage response.

Purpose of the Study:

  • To elucidate the molecular mechanism by which ATM-mediated phosphorylation of MDM2 leads to p53 activation.
  • To investigate the role of Ser429 phosphorylation in regulating MDM2 ubiquitin ligase activity and stability.

Main Methods:

  • X-ray crystallography to determine the structure of phospho-Ser429 MDM2.
  • In vitro biochemical assays to measure ubiquitin ligase activity.
  • Cellular experiments to assess MDM2 autoubiquitination and degradation in response to DNA damage.

Main Results:

  • Ser429 phosphorylation selectively enhances the activity of MDM2 homodimers, but not MDM2-MDMX heterodimers.
  • Structural analysis revealed that pS429 stabilizes a closed E2-ubiquitin conformation, boosting ubiquitin transfer.
  • In cells, Ser429 phosphorylation promotes MDM2 autoubiquitination and degradation upon DNA damage, while S429A substitution confers resistance to degradation.

Conclusions:

  • Ser429 phosphorylation acts as a molecular switch to enhance MDM2 homodimer activity and promote its self-degradation.
  • This mechanism facilitates rapid p53 stabilization following DNA damage, resolving controversies regarding MDM2 auto-degradation.