Studies of DNA replication and single-molecule dynamics

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In this application, I propose three interrelated projects in biophysics and statistical physics. The primary focus is on issues related to DNA replication, with both modeling and experimental aspects. The modeling aspects exploit the recent advances in experimental techniques that are giving large sets of data about the "replication state" (depicting, at a given region of the genome, which parts have and which have not been replicated at a given time). With large datasets and with the tools we have previously developed to understand replication, our group is uniquely positioned to answer many questions about how replication proceeds, under both normal and abnormal conditions. In particular, we shall begin to compare the replication "programs" of different organisms, to look at how replication changes during development, and to look at how replication is altered in mutants and in cancer cells. We are also extending our modeling formalism to be able to analyze different kinds of problems that arise during replication (such as nicks in a strand of DNA or double-strand breaks).