The successful duplication of a human cell requires error-free replication of the 3 X 109 bp genome and its equal segregation to daughter cells. This demanding task must be performed accurately millions of times over the lifetime of an individual, and its fidelity can be impaired by a variety of common genotoxic stresses, such as DNA-damaging UV light. Fortunately, cells have a variety of safeguards and repair mechanisms that act to preserve genomic integrity. Dr. Weiss's laboratory investigates the functions of mammalian genome maintenance pathways at the molecular, cellular, and organismal levels. Defects in these mechanisms can have severe consequences, including tumor development and infertility. Therefore, determining precisely how mammalian cells maintain genomic stability is of considerable significance.

The research in his laboratory focuses in part on one particular genome maintenance factor, the cell cycle checkpoint gene Hus1. To investigate the operation of the DNA damage response network involving Hus1, they inactivated Hus1 in the mouse, and found that loss of Hus1 causes embryonic lethality accompanied by spontaneous chromosomal abnormalities. Thus, Hus1 is essential for the maintenance of genomic stability. To determine the roles of Hus1 in post-natal development and tumorigenesis, they have now generated conditional knockout mice in which Hus1 can be deleted in specific adult tissues, such as the mammary gland, hematopoietic system, or skin. In cell culture studies and in vitro experimentation, they further examine the molecular mechanisms by which Hus1 mediates cellular responses to genotoxic stress, including DNA damage signaling and cell cycle control. To date, these studies have indicated that loss of Hus1 causes hypersensitivity to specific DNA damaging agents and that Hus1 is required for an S-phase checkpoint that represses DNA synthesis in response to genotoxic stress. The continued investigation of Hus1, as well as other novel factors, using molecular genetic and genomic technologies should provide important insights into how genome maintenance mechanisms contribute to normal development, tumor suppression, and cellular responses to anti-cancer drugs.