Converting a fertilized egg into an adult human requires TRILLIONS of cell divisions. Our research into the mechanisms that restrict nuclear DNA replication during cell division to one complete copy of the genome each time a cell divides revealed mechanisms by which some cells, such as trophoblast stem cells and megakaryoblasts, are developmentally programmed to differentiate into nonproliferating polyploid cells via 'endoreplication', a process in which mitosis is bypassed and a second S-phase ensues. Our research into the distinctions between stem cells, differentiated cells and cancer cells that regulate genome duplication led to the identification of genes essential to prevent 'unscheduled endoreplication', an event that promotes cancer, as well as genes essential to prevent 'DNA re-replication', an aberrant form of replication in which some regions are duplicated more than once during a single S-phase. Induction of DNA re-replication can selectively kill cancer cells with little or no harm to normal cells. This discovery led to the identification of a family of small molecules that can selectively kill cancer cells by disrupting lysosome homeostasis, a stable equilibrium essential for degrading and recycling cellular components to provide energy and nutrients for growth and proliferation. Our current goal is to determine the therapeutic potential of these molecules, and the mechanistic basis that distinguishes sensitive from insensitive cells.
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