J. Peter McPherson
Our well-being and survival depend on the faithful maintenance, replication and transmission of our genetic heritage through countless cell generations. Structural changes in DNA can occur as the result of endogenous metabolism processes or as a result of exposure to drugs, irradiation, or various environmental agents. Such structural alterations left unrepaired can lead to genetic mutations that compromise essential cellular processes or pose a genetic risk.
The cellular response to DNA damage is comprised of signaling networks that participate in surveillance, activation of cell cycle checkpoints, and recruitment of repair machinery. Components of these signaling pathways are mutated in various human syndromes that predispose individuals to genomic instability and cancer susceptibility. Furthermore, corruption of processes that sense and repair damage, arrest DNA replication, or eliminate damaged cells by apoptosis are now not only believed to contribute to neoplastic transformation of cancer cells, but also can compromise efficacy of therapeutic regimens that kill through activation of DNA damage pathways.
Work in my laboratory is focused on the identification of factors that promote genomic integrity as well as the characterization of molecular transactions that constitute the cellular response to DNA damage. A favoured strategy is the generation and characterization of deficient mouse models to elucidate the in vivo roles of candidate components of the DNA damage response in development, meiosis, haematopoiesis and cancer prevention. Knowledge of these molecular factors that contribute to genomic integrity and their involvement in normal physiology and in pathophysiology of disease will assist in the rational design of improved therapeutic strategies.