The role of nucleotide excision repair in DNA damage mediated apoptosis and cell cycle regulation

DNA damage has the capability to disrupt genomic stability and cause development of many disease conditions. Eliminating the DNA damage, either by DNA repair or programmed cell death (apoptosis), is essential in maintaining genetic fidelity and preventing disease occurrence. In addition, many anticancer drugs are targeted to the genomic DNA of cancer cells by generating DNA damage and enforcing apoptotic cell death. Therefore, determining the molecular mechanism of DNA damage-induced cellular responses has both clinical implication and scientific importance. We have studied the role of NER in cisplatin treatment-induced apoptotic cell death, the involvement of ATM activation, and the involvement of Bcl-2 family proteins in this process. Using both NF and NER-defective XPA and XPG cells, we demonstrated that the NER defects led to an altered cell cycle arrest and an increased apoptotic cell death after cisplatin treatment. The results suggest that the NER process may prevent cisplatin treatment-induced apoptotic cell death by assisting the autophosphorylation of the ATM protein and activating the ATM pathway, resulting in enhanced cell cycle arrest for DNA repair and cell survival after cisplatin treatment. These results further suggest that the XPC protein plays an important role in recruiting the ATM protein to genomic DNA and in linking the NER pathway with other cellular processes such as cell cycle regulation and apoptosis. Further studies involving the apoptotic pathway suggest that NER may prevent cisplatin treatment-induced apoptosis by activating the ATM protein through the NER repair intermediates, DSBs. This further activates the NF-kappaB pathway, causing induced expression of Bcl-xL and results in increased cell survival with cisplatin treatment. Therefore, the results obtained from this study provide an important insight into the mechanisms by which the NER process prevents DNA damage-induced apoptotic cell death and possible mechanisms for cancer cell drug resistance.