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Two- and Three-Dimensional Live Cell Imaging of DNA Damage Response Proteins
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DDB2 decides cell fate following DNA damage

Tanya Stoyanova1, Nilotpal Roy, Dragana Kopanja

  • 1Department of Biochemistry and Molecular Genetics (M/C 669), Cancer Center, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 23, 2009
PubMed

Insights

Damaged-DNA binding protein 2 (DDB2) regulates cell fate after DNA damage. DDB2 deficiency prevents apoptosis, promoting cell cycle arrest by stabilizing p21(Waf1/Cip1).

Area of Science:

  • Molecular Biology
  • Cell Biology
  • DNA Repair

Background:

  • Damaged-DNA binding protein 2 (DDB2), a xeroderma pigmentosum complementation group E protein, is involved in nucleotide excision repair (NER).
  • Previous work indicated DDB2 regulates p21(Waf1/Cip1) levels during NER.

Purpose of the Study:

  • To investigate the role of DDB2's p21(Waf1/Cip1) regulatory function in cellular responses to DNA damage.
  • To elucidate the mechanism by which DDB2 influences apoptosis versus cell cycle arrest.

Main Methods:

  • Analysis of DDB2-deficient cells treated with DNA-damaging agents.
  • Assessment of apoptosis, cell cycle arrest, p53 activation, pro-apoptotic gene expression, and E2F1-induced apoptosis.
  • Investigation of p21(Waf1/Cip1) accumulation and proteolysis.
  • Examination of Mdm2 involvement.

Main Results:

  • DDB2-deficient cells resist apoptosis and undergo cell cycle arrest despite p53 and pro-apoptotic gene activation.
  • Resistance to apoptosis in DDB2-deficient cells is linked to increased p21(Waf1/Cip1) accumulation.
  • DDB2 targets p21(Waf1/Cip1) for proteolysis, and Mdm2 plays a role distinct from its p53 regulation.

Conclusions:

  • DDB2's regulation of p21(Waf1/Cip1) proteolysis is crucial for determining cell fate (apoptosis or arrest) following DNA damage.
  • A novel regulatory loop involving DDB2, Mdm2, and p21(Waf1/Cip1) dictates cellular response to DNA damage.

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