Exposure to ubiquitous environmental carcinogens, such as poly aromatic hydrocarbons and UV light, is cause of human disease. It is well accepted that genetic mutations are an important step in the development of cancer. It has become clear that such mutations are introduced in part by error-prone DNA polymerases. In response to many environmental genotoxins, eukaryotic cells have evolved alternative methods of replicating damaged DNA, via the Trans-lesion synthesis (TLS) Polymerases, consisting of DNA Pol h, Pol k, Pol i, and Rev1. The TLS polymerases are recruited to stalled replication forks, where they mediate replication past damaged DNA. TLS is a central mechanism of replicating DNA that has been modified by exposure to environmental carcinogens, but the TLS is an inherently error-prone process. In addition, aberrant utilization of the TLS polymerases greatly predisposes to mutagenesis. Proper regulation and function of the TLS polymerases is thus a crucial mechanism of protecting genomic integrity. This research will study the mechanisms that regulate recruitment of TLS polymerases to sites of DNA damage in response to environmental genotoxins. In particular, we will test the hypothesis that Cdc7-mediated phosphorylation of Rad18 promotes formation of Rad18-Polh complexes and facilitates bypass of solar UV-induced DNA lesions. In addition, we will determine the mechanisms by which Rad18 ensures selection of the appropriate TLS polymerase in response to UV-induced (Polh) or BPDE- induced (PolK) DNA damage. These experiments will determine the significance of interactions between the TLS polymerases, Rad18, and Cdc7 and will help elucidate the mechanisms responsible for regulating TLS polymerases. Results of our studies will provide a novel link between normal and damage-induced replication and will help explain how environmental genotoxins contribute to mutagenesis.
. Exposure to environmental carcinogens poses a serious public health risk by compromising the integrity of cellular DNA. DNA damage causes gentic mutations and predisposes to a number of human diseases. This research will shed light into the cellular processes that mediate repair of environmentally induced DNA damage, thus aiding in the development of new strategies to prevent and to treat human disease resulting from damage to DNA.
|Durando, Michael; Tateishi, Satoshi; Vaziri, Cyrus (2013) A non-catalytic role of DNA polymerase ? in recruiting Rad18 and promoting PCNA monoubiquitination at stalled replication forks. Nucleic Acids Res 41:3079-93|