DDB2 decides cell fate following DNA damage

Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10690-5. doi: 10.1073/pnas.0812254106. Epub 2009 Jun 16.

Abstract

The xeroderma pigmentosum complementation group E (XP-E) gene product damaged-DNA binding protein 2 (DDB2) plays important roles in nucleotide excision repair (NER). Previously, we showed that DDB2 participates in NER by regulating the level of p21(Waf1/Cip1). Here we show that the p21(Waf1/Cip1) -regulatory function of DDB2 plays a central role in defining the response (apoptosis or arrest) to DNA damage. The DDB2-deficient cells are resistant to apoptosis in response to a variety of DNA-damaging agents, despite activation of p53 and the pro-apoptotic genes. Instead, these cells undergo cell cycle arrest. Also, the DDB2-deficient cells are resistant to E2F1-induced apoptosis. The resistance to apoptosis of the DDB2-deficient cells is caused by an increased accumulation of p21(Waf1/Cip1) after DNA damage. We provide evidence that DDB2 targets p21(Waf1/Cip1) for proteolysis. The resistance to apoptosis in DDB2-deficient cells also involves Mdm2 in a manner that is distinct from the p53-regulatory activity of Mdm2. Our results provide evidence for a new regulatory loop involving the NER protein DDB2, Mdm2, and p21(Waf1/Cip1) that is critical in deciding cell fate (apoptosis or arrest) upon DNA damage.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aclarubicin / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Cycle / physiology*
  • Cells, Cultured
  • Cisplatin / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage / physiology*
  • DNA Repair
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects
  • Flow Cytometry
  • HeLa Cells
  • Humans
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays

Substances

  • Antineoplastic Agents
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • DDB2 protein, human
  • DNA-Binding Proteins
  • Ddb2 protein, mouse
  • Tumor Suppressor Protein p53
  • Aclarubicin
  • Proto-Oncogene Proteins c-mdm2
  • Cisplatin