Developmental control of replication initiation and genome stability

Project Summary Every cell division requires the faithful duplication of genetic material from mother cell to daughter cell. Defects in the proper execution of the DNA replication program can directly result in the genome instability that is a hallmark of nearly all cancer cells. To ensure genome stability, the machinery responsible for DNA replication must be highly regulated. There must be enough flexibility built into the DNA replication program, however, to accommodate the dramatic changes in cell cycle and S phase progression that occur during the development of an organism. Understanding this regulation is imperative to determine how genome stability is maintained during development. We utilize the powerful developmental systems available in Drosophila to identify key regulators of the DNA replication program, with the ultimate goal of delineating the molecular underpinnings responsible for regulating genome duplication and stability during development. Our main focus is understanding how replication initiation is regulated to ensure genome stability. We have defined three key projects where the strength of our system positions us to make key insights. These include: 1) understanding the functional relationship between nuclear pore proteins and the Origin Recognition Complex (ORC). 2) Defining the key targets and molecular mechanisms Rif1 uses to influence replication initiation. 3) Identifying and characterizing posttranslational modifications of ORC that affect replication initiation.