Cancer consists of a multitude of specific disease states, all of which share in common: unregulated growth, failure to differentiate, and defects in chromosome biology. Defects in chromosomal biology and unregulated growth of cells are often the result of mis-regulation and/or mutations of the DNA replication machinery. However, it is becoming increasingly apparent that cancer is not driven solely by classical mutation but is also initiated and maintained by epigenetic changes. Epigenetic changes are alterations not associated with the nucleotide sequence of the genome but rather modifications of the nucleotides and DNA associated proteins that result in altered expression of genes. This altered expression is often the result of the formation of tightly packed DNA in the form of heterochromatin. Taken separately, both DNA replication and heterochromatin formation are important aspects of cancer biology. Understanding these two processes has been important for our understanding and treatment of cancer. Understanding how these two processes are linked promises to add a new and useful dimension to our ongoing efforts to confront cancer. The core aim of this proposal is to begin spell out how DNA replication and heterochromatin formation are linked through the study of Drosophila Mcm10. Study of this proteins on this level we allow us to begin to understand the network of interactions between DNA replication and heterochromatin formation. Using newly available technologies we will identify multiple alleles of MCM10 which will enable the separation of MCM10 function with respect to DNA replication and chromatin biology. Parsing these roles apart has the potential to lead to new therapies and diagnostics in treating cancer. Toward this end we propose to use the tractable genetic system Drosophila melanogaster to explore the following hypothesis: The Drosophila DNA replication factor MCM10 has separable functions in DNA replication and chromatin dynamics. We will address this hypothesis through the following specific aims: 1. Identify and characterize mutants in Drosophila MCM10 2. Assay MCM10 alleles for impacts on DNA replication 3. Assay MCM10 alleles for impacts on chromosome morphology and cell cycle 4. Assay the consequences of the MCM10 alleles on heterochromatin formation 5. Determine the consequences of these MCM10 alleles on interactions with other proteins
Understanding the link between how DNA is packaged appropriately and how DNA is copied will provide a broader understanding of how cancer develops in humans. Revealing the details of how these essential processes are linked will inform the diagnosis and treatment of cancer.
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