It is the overall goal of this research is to elucidate the mechanisms that underlie the development of resistance to cisplatin (DDP) and the multi-drug resistant phenotype that accompanies it. This project continues to focus on the role that loss of DNA mismatch repair (MMR) and its associated genomic instability plays in the development of resistance to this important drug. DDP is a mutagen, and we have demonstrated that even a single exposure of human cells to the drug is sufficient to generate clones in the surviving population that are highly resistant to many classes of chemotherapeutic agents. We found that many of the mutations induced by DDP are attributable to errors made by pol zeta during synthesis across DDP adducts in DNA. We have also discovered that DDP produces an error-prone state (EPS) in which DNA sequences not containing adducts are at increased risk of mutation as well. It is our hypothesis that DDP-induced genomic instability plays a central role in the development of the multidrug-resistant phenotype that accompanies emergence of resistance to DDP, and that this is augmented by defects in pathways that normally protect against genomic instability many of which are often disabled in tumor cells.
The specific aims are directed at the following questions: 1) What is the mechanism by which loss of MMR renders cells hypersensitive to the mutagenic effect of DDP? 2) What is the mechanism by which DDP causes mutations in DNA sequences not containing DDP adducts? 3) How important is DDP-induced mutagenesis relative to selection of pre-existing variants in the development of resistance? This project focuses on genomic instability produced by DDP. However, we have already demonstrated that oxidative stress and severe hypoxia both produce similar types of genomic instability in human cells. Thus, it is very likely that the mechanisms underlying the DDP-induced mutagenicity will be of fundamental importance to understanding the genomic instability produced by many types of cellular injury.
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