| In my thesis work, I discovered that DDB2 plays a major role in terminating the DNA damage response pathway upon UV allowing Nucleotide Excision Repair (NER) to take place. I found that DDB2 regulates p21 Waf1/Cip1 at both, transcriptional and protein stability. At transcriptional level DDB2 regulates p21Waf1/Cip1 trough p53, a transcriptional factor for p21Waf1/Cip1. DDB2-/- mouse embryonic fibroblasts (MEFs) are deficient in the proteolysis of p53S18P resulting in higher expression p21Waf1/Cip1. I provided evidence that the DDB2-/- participate in p21Waf1/Cip1 proteolysis as well. This accumulation of p21Waf1/Cip1 gives rise to NER deficiency in DDB2 -/- cells.;In addition to DNA repair, I discovered a novel role of DDB2 as a molecular switch in deciding cell fate (apoptosis or arrest) upon DNA damage. I found that DDB2 deficient cells are resistant to apoptosis upon treatment with DNA damaging agents--UV, cisplatin and aclarubicin. In the absence of DDB2, cells rather undergo cell cycle arrest than apoptosis. In consistence with the above mentioned findings, I observe much higher levels of p21Waf1/Cip1, previously shown as an inhibitor of apoptosis. Deletion of p21Waf1/Cip1 restores the apoptotic response in the DDB2-deficient cells.;Taken together, my results provide a novel genetic mechanism by which DDB2 controls Nucleotide Excision Repair and cell fate decision (apoptosis or arrest) upon DNA damage, by regulating p21Waf1/Cip1 level. |
