- Orsolya Kiraly
- Postdoctoral Associate, Engelward laboratory
- Department of Biological Engineering
- Massachusetts Institute of Technology
- 77 Massachusetts Ave, Cambridge, MA
- Lab: 617-750-7335 (Room 16-760)
- Email me through OpenWetWare
- Ph.D., Pathobiochemistry, Semmelweis University, Budapest, Hungary, 2008
- B.S., Molecular Biology, Eötvös Loránd University, Budapest, Hungary, 2002
My current work is about DNA damage and homologous recombination
I received my PhD for work on how rare mutations in pancreatic trypsin inhibitor contribute to chronic pancreatic inflammation. In the Engelward lab, my current work is aimed at homologous recombination in the pancreas in vivo.
While mitotic homologous recombination is an important DNA repair/tolerance mechanism, it can result in sequence rearrangements that can contribute to cancer. I am investigating the effects of DNA damaging chemicals, radiation, cell proliferation and DNA repair on homologous recombination in the pancreas.
The next question in my project is whether homologous recombination is induced by inflammation, which is a major risk factor for cancer.
Functional effects of sequence variants in promoters, introns, and protein-coding regions
In the lab of Miklos Sahin-Toth at Boston University, I was investigating the functional effects of mutations in SPINK1, the pancreatic secretory trypsin inhibitor. This inhibitor is an important line of defense against trypsin activity in the pancreas. It is important to inhibit any trypsin activity in the pancreas because trypsin activity can result in the activation of other digestive enzymes in a cascade reaction, which can lead to cell damage and pancreatic inflammation. We found that signal peptide mutations abolish the secretion of SPINK1 into pancreatic juice, and coding region mutations cause misfolding of the protein which is degraded intracellularly and is not secreted. In patients with these mutations, spontaneously activated trypsin is thus not inhibited by SPINK1, eventually resulting in autodigestion and inflammation.
At Semmelweis University I was working in a team studying the functional effects of polymorphisms in the promoter of the D4 dopamine receptor gene. This gene was the first one to be investigated in psychiatric genetics association studies, and its polymorphisms are associated with several personality traits and disorders such as ADHD. However, the functional effects of promoter polymorphisms (and thus the molecular basis of these associations) were not clear. With a reporter gene assay, we found that a duplication in the promoter decreases transcriptional efficiency, potentially influencing the number of receptor molecules and neurotransmission. However, the most widely studied SNP in the gene had no effect on gene expression in our assay. The apparent effect of this SNP in association studies is thus probably due to another variant which is in linkage disequilibrium with the candidate SNP.
My undergraduate thesis project at the Agricultural Biotechnology Research Center (in Gödöllő, Hungary) was aimed at generating host factor independent mutants of the 16-3 phage integrase by protein engineering. Integrases catalyze site-specific recombination which is harnessed in gene targeting. This project and the excellent mentoring I received at ABC gave me strong foundations in laboratory techniques in molecular biology and an interest in DNA metabolism and recombination.
See them on PubMed
Nemoda Z, Kiraly O, Barta C, Sasvari-Szekely M. Pharmacogenetic aspects of dopaminergic neurotransmission-related gene polymorphisms. In: Darvas F, Guttman A, Dormán G (eds): Chemical Genomics, Marcel Dekker Inc., New York, 2003, pp. 275-313.
Király O, Guan L, Sahin-Tóth M. Expression of recombinant proteins with uniform N termini using intein technology and aminopeptidase deficient Escherichia coli. In: Ming-Qun X, Evans T (eds): Heterologous Protein Expression in E. coli, Methods in Molecular Biology, Springer/Humana Press, in press
Laboratory tools and resources
Berglund:PCR_Additives A good list of PCR additives
The Suffering Gene is a very readable book about the various environmental exposures that can damage DNA
Cancer, the Evolutionary Legacy describes why we are susceptible to cancer even without environmental exposures
Correcting the Blueprint of Life: An Historical Account of the Discovery of DNA Repair Mechanisms by Errol C. Friedberg is a fascinating story of scientific discovery, great scientist personalities and the unpredictability of research
At the End of an Age by historian John Lukacs is not a scientific book, but it contains a deeply informed reflection on the nature of historical and scientific knowledge. Read a shorter essay on this here