Structural studies of metazoan origin licensing

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Project Summary Developing effective cancer therapies remains a significant challenge due to the heterogeneity of tumor physiology, cytotoxicity towards non-cancer cells, and the emergence of drug resistance, all of which hamper positive patient outcome. Thus, there is a critical need for novel anticancer agents with alternate mechanisms of action. Targeting the DNA replication initiation pathway is an underexplored strategy for cancer therapy. Origin licensing, the first step of DNA replication initiation during which the replicative helicase Mcm2-7 is loaded onto replication origins, is of particular interest because its inhibition is selectively cytotoxic towards cancer cell lines. However, no origin licensing inhibitors have been developed for clinical therapy yet, which is in part due to an incomplete mechanistic understanding of DNA replication initiation in metazoans. Contrary to S. cerevisiae, which has been used extensively to study replication initiation both at the biochemical and structural level, no structures of metazoan origin licensing intermediates containing Mcm2-7 on-pathway to helicase loading have been solved. How small-molecule origin licensing inhibitors bind and inhibit Mcm2-7 loading factors is likewise unknown. These gaps in knowledge have impeded the development of effective drug candidates targeting replication initiation. The goal of this proposal is to uncover structural insights into metazoan origin licensing. A deep understanding of metazoan origin licensing will aid in the development of small-molecule inhibitors targeting DNA replication initiation complexes and in defining the mechanisms by which these inhibitors act. These results will contribute to the long-term goal of developing origin licensing inhibitors as a new class of cancer drugs.