The overall focus of my lab is to understanding the regulation as well as cause of genomic instability in cancer and other diseases. Genomic instability is the most common hallmark of cancer, as well as the leading cause of miscarriages and birth defects. Understanding these signatures are both useful as prognostic indicators as well as therapeutic targets.

For over 20 years, I have been studying the tumor suppressor gene p53, and how it mediates the cellular response to genomic instability and cellular stress. The importance of this gene in tumorigenesis is most apparent by the fact that it is the most often inactivated gene in all cancers. In addition, Li Fraumeni Syndrome patients, which carry germline heterozygous p53 mutation/alteration, have a 50% likelihood of developing cancer by age 30, and 90% by age 60. While p53 has been studied for over 30 years, we still do not know how it suppresses tumorigenesis. Our lab utilizes both mouse and zebrafish animal models of Li Fraumeni syndrome to try to decipher the mechanism of p53 tumor suppression.

Sister chromatid cohesion (SCC) is an essential process for proper segregation of chromosomes. We have recently become involved in studying the effects that dysfunctional SCC have on embryonic development, as well as cancer predisposition. Roberts syndrome (RBS) is a rare autosomal developmental disease, that manifests in limb deformities, craniofacial defects, microcephaly, growth retardation, and mental retardation. RBS is due to homozygous inactivation of the gene ESCO2, involved in establishment of SCC during S-phase as the second strand is being synthesized. We are utilizing both zebrafish and mouse models of RBS to understand the pathogenesis of RBS and how SCC dysfunction affects human disease. We are also interested in why there is strong variability in disease severity (from prenatal lethality to asymptomatic adult individuals) amongst patient all null for Esco2. These studies are further assisted by over 70 zebrafish human disease models we have generated through our novel genome editing platform. We are also interested in knowing what determines the penetrance of a cancer syndrome individual. i.e. why does one LFS individual develop cancer at age 2, while another with the same mutation develops cancer at 60. Seeing that early diagnosis has have the strongest impact on patient survival, understanding this question would have great translational impact. Towards this, we have observed that mild SCC dysfunction strongly influences the timing of tumor onset. We are presently trying to understand the underlying mechanisms by which reduced SCC enhances tumor onset.

Percival S.M. and Parant J.M. Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo. (2016) Journal of Visualized Experiments (113). PMID: 27501381.

Lewis WR, Malarkey EB, Tritschler D, Bower R, Pasek RC, Porath JD, Birket SE, Saunier S, Antignac C, Knowles MR, Leigh MW, Zariwala MA, Challa AK, Kesterson RA, Rowe SM, Drummond IA, Parant JM, Hildebrandt F, Porter ME, Yoder BK, Berbari NF. Mutation of Growth Arrest Specific 8 Reveals a Role in Motile Cilia Function and Human Disease. (2016) PLoS Genet. 12(7):e1006220. PMCID: PMC4966937

Percival, S. M., Thomas, H. R., Amsterdam, A., Carroll, A. J., Lees, J. A., Yost, H. J. and Parant, J. M. Variations in sister chromatid cohesion dysfunction in ESCO2 mutant zebrafish reflects the phenotypic diversity of Roberts Syndrome. (2015) Disease models & mechanisms. 8(8), 941-55. PMCID: PMC4527282

Crittenden, F., Thomas, H. R., Parant, J. M. and Falany, C. N. Activity Suppression Behavior Phenotype in SULT4A1 Frameshift Mutant Zebrafish. (2015) Drug metabolism and disposition: the biological fate of chemicals 43, 1037-1044. PMCID: PMC4468436

Thomas H.R., Percival S.M., Yoder B.K., Parant J.M. High-throughput genome editing and phenotyping facilitated by high resolution melting curve analysis. (2014) PLoS one 9(12):e114632. PMCID: PMC4263700

Parant J.M., George S.A., Holden J.A., and Yost H. J. Genetic modeling of Li-Fraumeni syndrome in zebrafish. (2010) Disease Models and Mechanisms, 3(1-2):45-56.

Parant J.M., George S.A., Pryor R., Wittwer C. and Yost H.J. A rapid and efficient method of genotyping zebrafish mutants. (2009) Developmental Dynamics, 238(12):3168-74

Liu G., Parant J. M., Lang G., Chau P., Chavez-Reyes A., El-Naggar A.,K., Multani A., Chang S., and Lozano G. Chromosome stability, in the absence apoptosis, is critical for suppression of tumorogenesis in Trp53 mutant mice. (2004) Nature Genetics 36(1) 63-8

Lang G.A., Iwakuma T., Suh Y.A., Liu G., Rao V.A., Parant J.M., Valentin-Vega Y.A., Terzian T., Caldwell L.C., Strong L.C., El-Naggar A.K., Lozano G. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. (2004) Cell: 119(6):861-72.

Parant, J., Chavez-Reyes, A., Little, N.A., Yan, W., Reinke, V., Jochemsen, A.G., Lozano, G. (2001) Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a non-overlapping pathway with MDM2 to regulate p53. Nature Genetics 29(1), 92-95.