DDB2 decides cell fate following DNA damage
- 30 June 2009
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 106 (26), 10690-10695
- https://doi.org/10.1073/pnas.0812254106
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 p21Waf1/Cip1. Here we show that the p21Waf1/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 p21Waf1/Cip1 after DNA damage. We provide evidence that DDB2 targets p21Waf1/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 p21Waf1/Cip1 that is critical in deciding cell fate (apoptosis or arrest) upon DNA damage.Keywords
This publication has 37 references indexed in Scilit:
- PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complexGenes & Development, 2008
- MDMX Promotes Proteasomal Turnover of p21 at G1 and Early S Phases Independently of, but in Cooperation with, MDM2Molecular and Cellular Biology, 2008
- The Xeroderma Pigmentosum Group E Gene Product DDB2 Activates Nucleotide Excision Repair by Regulating the Level of p21Waf1/Cip1Molecular and Cellular Biology, 2008
- APC/CCdc20 Controls the Ubiquitin-Mediated Degradation of p21 in PrometaphaseMolecular Cell, 2007
- Ubiquitin-Independent Degradation of Cell-Cycle Inhibitors by the REGγ ProteasomeMolecular Cell, 2007
- Mdm2 Is Required for Inhibition of Cdk2 Activity by p21, Thereby Contributing to p53-Dependent Cell Cycle ArrestMolecular and Cellular Biology, 2007
- Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In VivoMolecular and Cellular Biology, 2007
- DDB1 is essential for genomic stability in developing epidermisProceedings of the National Academy of Sciences of the United States of America, 2007
- p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 ActivationCancer Research, 2006
- Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damageNature, 2002