David MacAlpine
Professor of Pharmacology and Cancer Biology

Our laboratory is interested in understanding the mechanisms by which the molecular architecture of the chromosome regulates fundamental biological processes such as replication and transcription. Specifically, how are replication, transcription and chromatin modification coordinated on a genomic scale to maintain genomic stability? We are addressing this question by using genomic, computational and biochemical approaches in the model organism Drosophila melanogaster.

DNA replication is an essential cell cycle event required for the timely and accurate duplication of chromosomes. Replication initiates at multiple sites (called origins of replication) distributed across each chromosome. The failure to properly regulate origin selection and activation may result in catastrophic genomic instability and potentially tumorigenesis. Recent metazoan genomic studies have demonstrated a correlation between time of DNA replication and transcriptional activity, with actively transcribed regions of the genome being replicated early. However, the underlying mechanism of this correlation remains unclear. By systematically characterizing the replication dynamics of multiple cell types, each with distinct transcriptional programs, we will be in a position to understand how these processes are coordinated.

Another goal of the laboratory is to identify the chromosomal features that direct and regulate metazoan DNA replication. Origins of DNA replication are marked by the formation of multi-protein complex, called the preRC. Despite conservation of the proteins that comprise the preRC in all eukaryotes, very little is known about the sequence elements required for the selection and regulation of metazoan origins. We are using genomic tiling microarrays to systematically map all the sites of preRC assembly in the Drosophila genome. The high resolution mapping of thousands of replication origins will provide an unprecedented opportunity to use both computational approaches and comparative genomics to identify cis-acting elements that may regulate replication.

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