Faculty: J. Peter McPherson, PhD
General Research Area: Molecular Pharmacology and Toxicology Causes and Consequences of Genomic Instability
Not taking graduate students in 2015-16
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.
Orieux G, Picault L, Slembrouck A, Roger JE, Guillonneau X, Sahel JA, Saule S, McPherson JP, Goureau O. Involvement of bcl-2-associated transcription factor 1 in the differentiation of early-born retinal cells. J Neurosci. 2014;34:1530-41.
Ondovcik SL, Tamblyn L, McPherson JP, Wells PG. Sensitivity to methylmercury toxicity is enhanced in oxoguanine glycosylase 1 knockout murine embryonic fibroblasts and is dependent on cellular proliferation capacity. Toxicol Appl Pharmacol. 2013;270:23-30.
MacPherson L, Tamblyn L, Rajendra S, Bralha F, McPherson JP, Matthews J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res. 2013; 41:1604-21.
Ondovcik SL, Tamblyn L, McPherson JP, Wells PG. Oxoguanine glycosylase 1 (OGG1) protects cells from DNA double-strand break damage following methylmercury (MeHg) exposure. Toxicol. Sci. 2012; 128: 272-83.
Sarras H, Alizadeh Azami S, McPherson JP. In search of a function for BCLAF1. Scientific World Journal 2010; 10: 1450-1461.
Mistry H, Tamblyn L, Butt H, Sisgoreo D, Gracias A, Larin M, Gopalakrishnan K, Hande MP and McPherson JP. UHRF1 is a genome caretakerthat facilitates the DNA damage response to γ-irradiation. Genome Integrity 2010; 1:7.
Tamblyn L, Li E, Sarras H, Srikanth P, Hande MP, McPherson JP. A role for Mus81 in the repair of chromium-induced DNA damage. Mutation Res. 2009; 660:57-65.
McPherson JP, Sarras H, Lemmers B, Migon E, Matysiak-Zablocki E, Hakem A, Calarco JA, Alizadeh Azami S, Cardoso R, Tamblyn L, Fish J, Sanchez O, Post M, and Hakem R. Essential role for Bclaf1 in lung development and immune system function. Cell Death Differen. 2009; 16: 331-339.
Mistry H, Gibson L, Yun JW, Sarras H, Tamblyn L, McPherson JP. Interplay between Np95 and Eme1 in the DNA damage response. Biochem. Biophys. Res. Commun. 2008; 375: 321-325.
McPherson JP, Hande MP, Lemmers B, Matysiak-Zablocki E, Migon E, Shehabeldin A, Porras A, d'Adda di Fagagna F, Karaskova J, Vukovic B, Sanchez-Sweatman OH, Khokha R, Squire J, and Hakem R. A role for Brca1 in Chromosome End Maintenance. Hum. Molec. Genet. 2006; 15:1-8.
McPherson JP, Tamblyn L, Elia A, Migon E, Shehabeldin, Matysiak-Zablocki E, Fish J, Kassam F, Lemmers B, Salmena L, Wakeham A, You-Ten A, Prakash Hande A, Bruneau BG and Hakem R. Lats2/Kpm is Required for Embryonic Development, Proliferation Control and Genomic Integrity. The EMBO J. 2004; 23:3677-3688.
McPherson JP, Lemmers B, Chahwan R, Pamidi A, Migon E, Matysiak-Zablocki E, Moynahan ME, Essers J, Hanada K, Poonepalli A, Sanchez-Sweatman O, Khokha R, Kanaar R, Jasin M, Hande MP, and Hakem R. Involvement of Mammalian Mus81 in Genome Integrity and Tumor Suppression. Science 2004; 304:1822-1826.
McPherson JP, Lemmers B, Hirao A, Migon E, Matysiak-Zablocki E, Sanchez-Sweatman O, Karaskova J, Abraham J, Hakem A, Tamblyn L, Bouchard D, Khokha R, Squire J, Hande MP, Mak TW, and Hakem R. Collaboration of Brca1 and Chk2 in tumorigenesis. Genes and Devel. 2004; 18:1144-1153.
University of Toronto
Department of Pharmacology and Toxicology
Room 4308, Medical Sciences Building
1 King's College Circle