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 multiple model systems including Drosophila melanogaster, Saccharomyces cerevisiae, and mammalian cell culture.
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. Origins of DNA replication are marked by the formation of multi-protein complex, called the pre-RC. Despite conservation of the proteins that comprise the pre-RC in all eukaryotes, very little is known about the sequence and chromatin features required for the selection and regulation of metazoan origins. We are using next-generation sequencing based approaches to comprehensively identify and survey the chromatin features associated with start sites of DNA replication.
