Areas of Interest
Ligase 3 (Lig3) is unique among the three mammalian DNA ligases in that its gene encodes four alternative splice isoforms directed to either the mitochondria or the nucleus. Identified as the only mitochondrial ligase in higher eukaryotes, Lig3 is essential for the replication and maintenance of the mitochondrial genome. Unlike mitochondrial Lig3, the role of nuclear Lig3 is relatively unknown. In the nucleus, Lig3 is capable of catalyzing the reactions of DNA Lig1 and Lig4, indicating there are overlapping substrate specificities amongst these enzymes. Although functional overlap between Lig3 and other nuclear ligases would seem to be advantageous, nuclear Lig3 has contributed to erroneous activities such as reciprocal chromosomal translocations and DNA deletions. While great progress has been made investigating the physiological role and importance of Lig3, a systematic characterization of its catalytic mechanism is lacking. To develop a baseline understanding of the enzyme, the minimal kinetic mechanism will be determined using various substrates containing single and double-strand DNA breaks. This kinetic framework will allow for the characterization of the various Lig3 isoforms as well as the catalytic contributions of Lig3-binding proteins. This information will provide a deeper understanding of backup ligation pathways and the consequences of imbalances in the levels of different DNA ligases. The erroneous ligation catalyzed by nuclear Lig3 also makes it a possible target for novel inhibitors that could be used to repress such ligation events. Inhibition of Lig3 could be feasible, since the nuclear and mitochondrial isoforms interact with different protein partners.
Justin McNally and Patrick J. O'Brien; In Vitro Characterization of Human DNA Ligase IIIβ. Presented at the 33rd Midwest Enzyme Chemistry Conference (MECC), Loyola University, Chicago. (2013)
Justin McNally and Patrick J. O'Brien; Catalytic Insights into Human DNA Ligase III. Presented at the 16th Annual Midwest DNA Repair Symposium, Wayne State University. (2014)
Justin McNally and Patrick J. O'Brien; Kinetic Characterization of Human DNA Ligase III. Presented at the 34th Midwest Enzyme Chemistry Conference (MECC), Northwestern University, Evanston, IL. (2014)
Justin McNally and Patrick J. O'Brien; Kinetic Characterization of Human DNA Ligase III. Presented at the 17th Annual Midwest DNA Repair Symposium, Indiana University. (2015)
Justin McNally and Patrick J. O'Brien; Comparative Analysis of DNA Ligase III Isoforms. Presented at the 35th Midwest Enzyme Chemistry Conference (MECC), Illinois Institute of Technology, Chicago, IL. (2015)
Honors & Awards
Bou-Abdallah F, McNally J, Liu XX, Melman A. Oxygen catalyzed mobilization of iron from ferritin by iron(III) chelate ligands. Chem Commun (Camb). 2011;47(2):731-3.
Tyson Terpstra, Justin McNally, Thi hong Lien Han, Nguyet Thanh Ha Duong, Jean-Michel El-Hage Chahine, and Fadi Bou-Abdallah, Direct Thermodynamic and Kinetic Measurements of Fe2+and Zn2+Binding to Human Serum Transferrin. J. Inorg. Biochem. 2014:136:24-32.
Justin McNally, Paolo Arosio and Fadi Bou-Abdallah, Stability and Functionality of H/L Heteropolymer Ferritins Responsible for Hereditary Ferritinopathy Disorder. Manuscript in preparation.