Karin Nitiss, PhD
Research Assistant Professor
Department of Biomedical Sciences
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1601 Parkview Ave., E521 NMRL, Rockford, IL 61107
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About
Research Interests:
Dr. Nitiss participates in the research program directed by John Nitiss, PhD, in the Department of Biopharmaceutical Sciences in the UIC College of Pharmacy.
DNA topoisomerases are the targets of active FDA approved anti-cancer agents and include agents such as irinotecan and topotecan that target topoisomerase I and etoposide and doxorubicin that target topoisomerase II. Topoisomerase targeting anti-cancer drugs inhibit a key step in the topoisomerase reaction pathway and trap the enzyme as a covalent protein: DNA adduct. Since trapped protein: DNA adducts can arise by natural processes as well as by small molecule enzyme inhibitors, there are a wealth of pathways that can repair this unique form of DNA damage. Our work has concentrated on specialized topoisomerase repair enzymes such as Tdp1 and Tdp2, as well as other repair endonucleases such as Mre11, Slx1/Slx4, and XPG. We have developed novel substrates for assessing the activity of repair nucleases on protein: DNA complexes. These substrates have been used to demonstrate that Tdp1 is able to process the covalent complexes that arise from trapping topoisomerase II, and demonstrated that proteolysis is required to generate substrates that can be further processed by repair nucleases. A major unsolved problem is how cellular repair pathways can differentiate topoisomerases that are trapped by small molecule inhibitors from normal enzyme intermediates. We hypothesized that repair nucleases interact with other proteins to detect trapped complexes, and have identified proteins that physically interact with repair enzymes in an effort to reconstruct complete pathways for repairing topoisomerase induced DNA damage. Our efforts may lead to the identification of novel markers that predict clinical response to topoisomerase targeting anti-cancer drugs, as well the development of novel clinical agents that enhance the activity of agents such as etoposide and doxorubicin.
Selected Publications
Nitiss, K. C., & Nitiss, J. L. (2014). Twisting and ironing: Doxorubicin cardiotoxicity by mitochondrial DNA damage. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 20(18), 4737-4739. doi:10.1158/1078-0432.CCR-14-0821 [doi]
Katyal, S., Lee, Y., Nitiss, K. C., Downing, S. M., Li, Y., Shimada, M., et al. (2014). Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nature Neuroscience, 17(6), 813-821. doi:10.1038/nn.3715 [doi]
Gao, R., Schellenberg, M. J., Huang, S. Y., Abdelmalak, M., Marchand, C., Nitiss, K. C., et al. (2014). Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2.DNA and Top2.RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2). The Journal of Biological Chemistry, 289(26), 17960-17969. doi:10.1074/jbc.M114.565374 [doi]
Bahmed, K., Seth, A., Nitiss, K. C., & Nitiss, J. L. (2011). End-processing during non-homologous end-joining: A role for exonuclease 1. Nucleic Acids Research, 39(3), 970-978. doi:10.1093/nar/gkq886 [doi]
He, X., van Waardenburg, R. C., Babaoglu, K., Price, A. C., Nitiss, K. C., Nitiss, J. L., et al. (2007). Mutation of a conserved active site residue converts tyrosyl-DNA phosphodiesterase I into a DNA topoisomerase I-dependent poison. Journal of Molecular Biology, 372(4), 1070-1081. doi:S0022-2836(07)00985-0 [pii]