Bio:

I started my scientific journey as a MSc student in Dr. András Váradi’s laboratory in Hungary, at the Institute of Enzymology. I used a fruit fly model to study the mechanism of ABC C-type transporters, which are important in multidrug resistance in cancer. I then switched continents and started my Ph.D. at Uniformed Services University in the United States. I became interested in RNA Biology and joined Dr. Markos Koutmos’ laboratory to expand my existing biochemistry knowledge and learn structural biology. I functionally and structurally characterized what at that time was a novel group of enzymes, Protein-only RNase Ps (PRORP). These enzymes catalyze the 5’ end cleavage of pre-tRNAs and partially or completely replace the ribozyme RNase P in some Eukaryotes. As an American Heart Association pre-doctoral fellow, I also linked PRORP function in human mitochondria to mitochondrial diseases. For my postdoctoral training, I wanted to continue expanding my work in RNA biology and learn high-throughput sequencing methods. As an NIGMS PRAT postdoctoral fellow in the laboratory of Dr. Nicholas Guydosh at the NIDDK (NIH), I studied the role of RNA cleavage by RNase L in the innate immune response. I investigated the molecular mechanisms that occurs after RNA fragmentation by RNase L. I found that RNA fragmentation leads to translational stress that in turn trigger downstream signaling and cell death.  During this time, I also received the K99/R00 award from NIGMS. The Karasik laboratory will open in August 2025 and will investigate the molecular mechanisms and cellular outcomes of RNase activity related to human health and disease.

Research Overview:

I was always fascinated by the fast pace of discoveries in RNA Biology and how rapidly findings can be translated into the clinics. And after all, RNAs might have been the first molecules to form life on Earth!  Thus, I combined this interest of RNA Biology with my excitement for biochemistry to study molecular mechanism related to human health and disease.

How does RNA cleavage influence human health and disease?

Our laboratory is broadly interested in the molecular mechanisms and consequences of RNA cleavage in the cell. For instance, widespread RNA cleavage and decay is employed by both the host and viruses to promote or suppress the innate immune response. However, it remains unanswered how and why both benefit from such a widespread endonucleolytic cleavage, and many molecular mechanisms of it are unknown. 

Presence of pathogens can trigger the activation of a host endonuclease, RNase L. Activated RNase L cleaves both viral and host RNAs in single stranded regions, serving as a key component in the innate immune response. Besides this fundamental role in the response against viral infections, mutations in the RNASEL gene are associated with cancer, bacterial infections and autoimmunity. The current questions we are investigating:

1. How do RNases, such as RNase L, select their targets? How is RNase activity modulated? Can we use this knowledge to guide future therapies?

2. How does RNase activity influence physiological changes in the cell?

3. How do mutations in RNases affect outcomes of human diseases? 

To answer these questions, we apply a variety of molecular techniques including enzymology, structural biology and high-throughput sequencing (RNA-seq, ribosome profiling, Nanopore long-read sequencing) in vitro and in cell cultures.

Select Publications:

Full list of publications

Agnes Karasik and Nicholas R Guydosh, The unusual role of Ribonuclease L in innate immunity, WIREs RNA, 2024

Agnes Karasik, Hernan A. Lorenzi, Andrew V. DePass, Nicholas R Guydosh, Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response, Cell Reports, 2024

Agnes Karasik, Grant D. Jones, Andrew V. DePass, Nicholas R Guydosh, RNase L mediated antiviral response triggers translation of non-coding mRNA sequences, Nucleic Acids Research, 2021

Agnes Karasik, Catherine A. Wilhelm, Carol Fierke, Markos Koutmos, Disease-associated mutations in mitochondrial precursor tRNAs affect binding, m1R9 methylation and tRNA processing by mtRNase P, RNA, 2021

Agnes Karasik, Carol A. Fierke, Markos Koutmos, Interplay between substrate recognition, 5’ end tRNA processing and methylation activity of human mitochondrial RNase P, RNA, 2019

Agnes Karasik, András Váradi, Flóra Szeri, In vitro transport of methotrexate by Drosophila Multidrug Resistance-associated Protein, PLOS One, 2018

Agnes Karasik, Kaitlyn Ledwitch, Tamás Arányi, András Váradi, Arthur Roberts, Flóra Szeri, Boosted coupling of ATP hydrolysis to substrate transport upon cooperative estradiol-17-ß-D-glucuronide binding in a Drosophila ABCC transporter, FASEB Journal, 2017

Agnes Karasik, Aranganathan Shanmuganathan, Michael J. Howard, Carol A. Fierke, Markos Koutmos, Nuclear Protein-only ribonuclease P 2 Structure and Biochemical Characterization Provide Insight into the Conserved Properties of tRNA 5’-end Processing Enzymes, Journal of Molecular Biology, 2016

Aditya Sen*, Agnes Karasik*, Aranganathan Shanmuganathan, Elena Mirkovic, Markos Koutmos, Rachel T. Cox, Loss of the mitochondrial protein-only ribonuclease P complex causes aberrant tRNA processing and lethality in Drosophila, Nucleic Acids Research, 2016