Genomic mapping of replication origins in melanocytes and melanoma

Yale University, New Haven CT

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Abstract

Cancer is characterized by defective regulation of cellular proliferative potential. In contrast to the explosion of knowledge in other aspects of genetic control of cellular growth, only a few replication origins have been studied in detail in higher eukaryotes. Even less is known of the control and timing of the initiation of replication on a genomic scale, in large part because of the lack of suitable assays. Altered control of DNA replication may lead to uncontrolled proliferation and cancer by several possible mechanisms including delay in timing of the use of some replication origins relative to the start of S phase, a change in order of use of replication origins, or a change in frequency of use of specific origins. The distribution of origins of replication initiation has not been approached in the genomic sense in any eukaryotic cell, and is potentially relevant to the pathogenesis of cancer. In the present pilot proposal, we intend to develop an innovative method for simultaneously mapping replication origins across the genome, and to demonstrate selective recovery of known origins. We will apply the method to compare the pattern of origins used normal melanocytes and nodular melanoma The information from such a survey will potentially yield new insights into the global genetic differences between normal and malignant cells.