Our bodies are subjected to a barrage of potentially damaging agents every day. Some of these agents come from the environment surrounding us and some are generated inside us by the very act of living. Fortunately for our longevity, systems have evolved within our cells that repair much of the damage that we experience. One of the last lines of defense against permanent damage to our genetic code resides in a class of enzymes called the Y-family polymerases. These molecular motors are unique in their ability to deal with damaged DNA. However, given the veritable jungle of types of DNA lesions, there are many things that we do not yet understand concerning how the Y-family polymerases repair damage. In an effort to address the myriad of unanswered questions regarding Y-family polymerase bypass of damaged DNA, this proposal will study the ability of a model Y-family polymerase called Dpo4 to copy past a very common form of DNA damage that results from exposure to agents that are not only found in the environment but are also used in chemotherapeutic regimes to treat multiple types of cancer. Kinetic analyses will be combined with x-ray crystallographic studies in order to couple structure with function. ? ? ?
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