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Bio

Honors & Awards


  • Best Poster Award, Gordon Research Conference on Post-transcriptional Gene Regulation (2018)
  • The Helena Anna Henzl-Gabor Young Women in Science Fund for Postdoctoral Scholars Travel Grant, Stanford University (2017)
  • Harden Bursary, EMBO Conference??Helicases and Nucleic Acid Translocases (2013)
  • RNA Society Poster Award, FASEB Conference on Nucleic Acid Enzymes (2012)
  • Travel Award, University of Texas at Austin (2010, 2012)
  • Eakin Fellowship, University of Texas at Austin (2010)
  • Eastern European Scholarship, Ev. Studienwerk e.V. Villigst (Germany) (2004?2008)

Education & Certifications


  • PhD, University of Texas at Austin, Biochemistry (2014)
  • Diplom, Julius Maximilian University of Würzburg (2009)

Publications

All Publications


  • Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis. Nature communications Liu, X., Sun, T., Shcherbina, A., Li, Q., Jarmoskaite, I., Kappel, K., Ramaswami, G., Das, R., Kundaje, A., Li, J. B. 2021; 12 (1): 2165

    Abstract

    Adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR enzymes occurs in double-stranded RNAs. Despite a compelling need towards predictive understanding of natural and engineered editing events, how the RNA sequence and structure determine the editing efficiency and specificity (i.e., cis-regulation) is poorly understood. We apply a CRISPR/Cas9-mediated saturation mutagenesis approach to generate libraries of mutations near three natural editing substrates at their endogenous genomic loci. We use machine learning to integrate diverse RNA sequence and structure features to model editing levels measured by deep sequencing. We confirm known features and identify new features important for RNA editing. Training and testing XGBoost algorithm within the same substrate yield models that explain 68 to 86 percent of substrate-specific variation in editing levels. However, the models do not generalize across substrates, suggesting complex and context-dependent regulation patterns. Our integrative approach can be applied to larger scale experiments towards deciphering the RNA editing code.

    View details for DOI 10.1038/s41467-021-22489-2

    View details for PubMedID 33846332

  • ATP utilization by a DEAD-box protein during refolding of a misfolded group I intron ribozyme. The Journal of biological chemistry Jarmoskaite, I. n., Tijerina, P. n., Russell, R. n. 2020

    Abstract

    DEAD-box helicase proteins perform ATP-dependent rearrangements of structured RNAs throughout RNA biology. Short RNA helices are unwound in a single ATPase cycle, but the ATP requirement for more complex RNA structural rearrangements is unknown. Here we measure the amount of ATP used for native refolding of a misfolded group I intron ribozyme by CYT-19, a Neurospora crassa DEAD-box protein that functions as a general chaperone for mitochondrial group I introns. By comparing the rates of ATP hydrolysis and ribozyme refolding, we find that several hundred ATP molecules are hydrolyzed during refolding of each ribozyme molecule. After subtracting non-productive ATP hydrolysis that occurs in the absence of ribozyme refolding, we find that approximately 100 ATPs are hydrolyzed per refolded RNA as a consequence of interactions specific to the misfolded ribozyme. This value is insensitive to changes in ATP and CYT-19 concentration and decreases with decreasing ribozyme stability. Because of earlier findings that ~90% of global ribozyme unfolding cycles lead back to the kinetically preferred misfolded conformation and are not observed, we estimate that each global unfolding cycle consumes ~10 ATPs. Our results indicate that CYT-19 functions as a general RNA chaperone by using a stochastic, energy-intensive mechanism to promote RNA unfolding and refolding, suggesting an evolutionary convergence with protein chaperones.

    View details for DOI 10.1074/jbc.RA120.015029

    View details for PubMedID 33262215

  • How to measure and evaluate binding affinities. eLife Jarmoskaite, I. n., AlSadhan, I. n., Vaidyanathan, P. P., Herschlag, D. n. 2020; 9

    Abstract

    Quantitative measurements of biomolecule associations are central to biological understanding and are needed to build and test predictive and mechanistic models. Given the advances in high-throughput technologies and the projected increase in the availability of binding data, we found it especially timely to evaluate the current standards for performing and reporting binding measurements. A review of 100 studies revealed that in most cases essential controls for establishing the appropriate incubation time and concentration regime were not documented, making it impossible to determine measurement reliability. Moreover, several reported affinities could be concluded to be incorrect, thereby impacting biological interpretations. Given these challenges, we provide a framework for a broad range of researchers to evaluate, teach about, perform, and clearly document high-quality equilibrium binding measurements. We apply this framework and explain underlying fundamental concepts through experimental examples with the RNA-binding protein Puf4.

    View details for DOI 10.7554/eLife.57264

    View details for PubMedID 32758356

  • A Quantitative and Predictive Model for RNA Binding by Human Pumilio Proteins MOLECULAR CELL Jarmoskaite, I., Denny, S. K., Vaidyanathan, P. P., Becker, W. R., Andreasson, J. L., Layton, C. J., Kappel, K., Shivashankar, V., Sreenivasan, R., Das, R., Greenleaf, W. J., Herschlag, D. 2019; 74 (5): 966-+
  • Demonstration of protein cooperativity mediated by RNA structure using the human protein PUM2 RNA Becker, W. R., Jarmoskaite, I., Vaidyanathan, P. P., Greenleaf, W. J., Herschlag, D. 2019; 25 (6): 702?12
  • Blind tests of RNA-protein binding affinity prediction PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kappel, K., Jarmoskaite, I., Vaidyanathan, P. P., Greenleaf, W. J., Herschlag, D., Das, R. 2019; 116 (17): 8336?41
  • Quantitative high-throughput tests of ubiquitous RNA secondary structure prediction algorithms via RNA/protein binding bioRxiv Becker, W. R., Jarmoskaite, I., Kappel, K., Vaidyanathan, P. P., Denny, S. K., Das, R., Greenleaf, W. J., Herschlag, D. 2019

    View details for DOI 10.1101/571588

  • Lessons from Enzyme Kinetics Reveal Specificity Principles for RNA-Guided Nucleases in RNA Interference and CRISPR-Based Genome Editing. Cell systems Bisaria, N., Jarmoskaite, I., Herschlag, D. 2017; 4 (1): 21-29

    Abstract

    RNA-guided nucleases (RGNs) provide sequence-specific gene regulation through base-pairing interactions between a small RNA guide and target RNA or DNA. RGN systems, which include CRISPR-Cas9 and RNA interference (RNAi), hold tremendous promise as programmable tools for engineering and therapeutic purposes. However, pervasive targeting of sequences that closely resemble the intended target has remained a major challenge, limiting the reliability and interpretation of RGN activity and the range of possible applications. Efforts to reduce off-target activity and enhance RGN specificity have led to a collection of empirically derived rules, which often paradoxically include decreased binding affinity of the RNA-guided nuclease to its target. We consider the kinetics of these reactions and show that basic kinetic properties can explain the specificities observed in the literature and the changes in these specificities in engineered systems. The kinetic models described provide a foundation for understanding RGN targeting and a necessary conceptual framework for their rational engineering.

    View details for DOI 10.1016/j.cels.2016.12.010

    View details for PubMedID 28125791

  • Science Educational Outreach Programs That Benefit Students and Scientists. PLoS biology Clark, G. n., Russell, J. n., Enyeart, P. n., Gracia, B. n., Wessel, A. n., Jarmoskaite, I. n., Polioudakis, D. n., Stuart, Y. n., Gonzalez, T. n., MacKrell, A. n., Rodenbusch, S. n., Stovall, G. M., Beckham, J. T., Montgomery, M. n., Tasneem, T. n., Jones, J. n., Simmons, S. n., Roux, S. n. 2016; 14 (2): e1002368

    Abstract

    Both scientists and the public would benefit from improved communication of basic scientific research and from integrating scientists into education outreach, but opportunities to support these efforts are limited. We have developed two low-cost programs-"Present Your PhD Thesis to a 12-Year-Old" and "Shadow a Scientist"-that combine training in science communication with outreach to area middle schools. We assessed the outcomes of these programs and found a 2-fold benefit: scientists improve their communication skills by explaining basic science research to a general audience, and students' enthusiasm for science and their scientific knowledge are increased. Here we present details about both programs, along with our assessment of them, and discuss the feasibility of exporting these programs to other universities.

    View details for PubMedID 26844991

  • Hexapeptides That Inhibit Processing of Branched DNA Structures Induce a Dynamic Ensemble of Holliday Junction Conformations JOURNAL OF BIOLOGICAL CHEMISTRY Cannon, B., Kachroo, A. H., Jarmoskaite, I., Jayaram, M., Russell, R. 2015; 290 (37): 22734-22746

    Abstract

    Holliday junctions are critical intermediates in DNA recombination, repair, and restart of blocked replication. Hexapeptides have been identified that bind to junctions and inhibit various junction-processing enzymes, and these peptides confer anti-microbial and anti-tumor properties. Earlier studies suggested that inhibition results from stabilization of peptide-bound Holliday junctions in the square planar conformation. Here, we use single molecule fluorescence resonance energy transfer (smFRET) and two model junctions, which are AT- or GC-rich at the branch points, to show that binding of the peptide KWWCRW induces a dynamic ensemble of junction conformations that differs from both the square planar and stacked X conformations. The specific features of the conformational distributions differ for the two peptide-bound junctions, but both junctions display greatly decreased Mg(2+) dependence and increased conformational fluctuations. The smFRET results, complemented by gel mobility shift and small angle x-ray scattering analyses, reveal structural effects of peptides and highlight the sensitivity of smFRET for analyzing complex mixtures of DNA structures. The peptide-induced conformational dynamics suggest multiple stacking arrangements of aromatic amino acids with the nucleobases at the junction core. This conformational heterogeneity may inhibit DNA processing by increasing the population of inactive junction conformations, thereby preventing the binding of processing enzymes and/or resulting in their premature dissociation.

    View details for DOI 10.1074/jbc.M115.663930

    View details for PubMedID 26209636

  • DEAD-box protein CYT-19 is activated by exposed helices in a group I intron RNA PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jarmoskaite, I., Bhaskaran, H., Seifert, S., Russell, R. 2014; 111 (29): E2928-E2936

    Abstract

    DEAD-box proteins are nonprocessive RNA helicases and can function as RNA chaperones, but the mechanisms of their chaperone activity remain incompletely understood. The Neurospora crassa DEAD-box protein CYT-19 is a mitochondrial RNA chaperone that promotes group I intron splicing and has been shown to resolve misfolded group I intron structures, allowing them to refold. Building on previous results, here we use a series of tertiary contact mutants of the Tetrahymena group I intron ribozyme to demonstrate that the efficiency of CYT-19-mediated unfolding of the ribozyme is tightly linked to global RNA tertiary stability. Efficient unfolding of destabilized ribozyme variants is accompanied by increased ATPase activity of CYT-19, suggesting that destabilized ribozymes provide more productive interaction opportunities. The strongest ATPase stimulation occurs with a ribozyme that lacks all five tertiary contacts and does not form a compact structure, and small-angle X-ray scattering indicates that ATPase activity tracks with ribozyme compactness. Further, deletion of three helices that are prominently exposed in the folded structure decreases the ATPase stimulation by the folded ribozyme. Together, these results lead to a model in which CYT-19, and likely related DEAD-box proteins, rearranges complex RNA structures by preferentially interacting with and unwinding exposed RNA secondary structure. Importantly, this mechanism could bias DEAD-box proteins to act on misfolded RNAs and ribonucleoproteins, which are likely to be less compact and more dynamic than their native counterparts.

    View details for DOI 10.1073/pnas.1404307111

    View details for Web of Science ID 000339310700004

    View details for PubMedID 25002474

  • RNA Helicase Proteins as Chaperones and Remodelers ANNUAL REVIEW OF BIOCHEMISTRY, VOL 83 Jarmoskaite, I., Russell, R. 2014; 83: 697-725

    Abstract

    Superfamily 2 helicase proteins are ubiquitous in RNA biology and have an extraordinarily broad set of functional roles. Central among these roles are the promotion of rearrangements of structured RNAs and the remodeling of ribonucleoprotein complexes (RNPs), allowing formation of native RNA structure or progression through a functional cycle of structures. Although all superfamily 2 helicases share a conserved helicase core, they are divided evolutionarily into several families, and it is principally proteins from three families, the DEAD-box, DEAH/RHA, and Ski2-like families, that function to manipulate structured RNAs and RNPs. Strikingly, there are emerging differences in the mechanisms of these proteins, both between families and within the largest family (DEAD-box), and these differences appear to be tuned to their RNA or RNP substrates and their specific roles. This review outlines basic mechanistic features of the three families and surveys individual proteins and the current understanding of their biological substrates and mechanisms.

    View details for DOI 10.1146/annurev-biochem-060713-035546

    View details for Web of Science ID 000348432500027

    View details for PubMedID 24635478

  • The Long-Range P3 Helix of the Tetrahymena Ribozyme Is Disrupted during Folding between the Native and Misfolded Conformations JOURNAL OF MOLECULAR BIOLOGY Mitchell, D., Jarmoskaite, I., Seval, N., Seifert, S., Russell, R. 2013; 425 (15): 2670-2686

    Abstract

    RNAs are prone to misfolding, but how misfolded structures are formed and resolved remains incompletely understood. The Tetrahymena group I intron ribozyme folds in vitro to a long-lived misfolded conformation (M) that includes extensive native structure but is proposed to differ in topology from the native state (N). A leading model predicts that exchange of the topologies requires unwinding of the long-range, core helix P3, despite the presence of P3 in both conformations. To test this model, we constructed 16 mutations to strengthen or weaken P3. Catalytic activity and in-line probing showed that nearly all of the mutants form the M state before folding to N. The P3-weakening mutations accelerated refolding from M (3- to 30-fold) and the P3-strengthening mutations slowed refolding (6- to 1400-fold), suggesting that P3 indeed unwinds transiently. Upon depletion of Mg(2+), the mutations had analogous effects on unfolding from N to intermediates that subsequently fold to M. The magnitudes for the P3-weakening mutations were larger than in refolding from M, and small-angle X-ray scattering showed that the ribozyme expands rapidly to intermediates from which P3 is disrupted subsequently. These results are consistent with previous results indicating unfolding of native peripheral structure during refolding from M, which probably permits rearrangement of the core. Together, our results demonstrate that exchange of the native and misfolded conformations requires loss of a core helix in addition to peripheral structure. Further, the results strongly suggest that misfolding arises from a topological error within the ribozyme core, and a specific topology is proposed.

    View details for DOI 10.1016/j.jmb.2013.05.008

    View details for Web of Science ID 000322296400005

    View details for PubMedID 23702292

  • Toward a molecular understanding of RNA remodeling by DEAD-box proteins RNA BIOLOGY Russell, R., Jarmoskaite, I., Lambowitz, A. M. 2013; 10 (1): 44-55

    Abstract

    DEAD-box proteins are superfamily 2 helicases that function in all aspects of RNA metabolism. They employ ATP binding and hydrolysis to generate tight, yet regulated RNA binding, which is used to unwind short RNA helices non-processively and promote structural transitions of RNA and RNA-protein substrates. In the last few years, substantial progress has been made toward a detailed, quantitative understanding of the structural and biochemical properties of DEAD-box proteins. Concurrently, progress has been made toward a physical understanding of the RNA rearrangements and folding steps that are accelerated by DEAD-box proteins in model systems. Here, we review the recent progress on both of these fronts, focusing on the mitochondrial DEAD-box proteins Mss116 and CYT-19 and their mechanisms in promoting the splicing of group I and group II introns.

    View details for DOI 10.4161/rna.22210

    View details for Web of Science ID 000314452200006

    View details for PubMedID 22995827

  • Solution structures of DEAD-box RNA chaperones reveal conformational changes and nucleic acid tethering by a basic tail PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Mallam, A. L., Jarmoskaite, I., Tijerina, P., Del Campo, M., Seifert, S., Guo, L., Russell, R., Lambowitz, A. M. 2011; 108 (30): 12254-12259

    Abstract

    The mitochondrial DEAD-box proteins Mss116p of Saccharomyces cerevisiae and CYT-19 of Neurospora crassa are ATP-dependent helicases that function as general RNA chaperones. The helicase core of each protein precedes a C-terminal extension and a basic tail, whose structural role is unclear. Here we used small-angle X-ray scattering to obtain solution structures of the full-length proteins and a series of deletion mutants. We find that the two core domains have a preferred relative orientation in the open state without substrates, and we visualize the transition to a compact closed state upon binding RNA and adenosine nucleotide. An analysis of complexes with large chimeric oligonucleotides shows that the basic tails of both proteins are attached flexibly, enabling them to bind rigid duplex DNA segments extending from the core in different directions. Our results indicate that the basic tails of DEAD-box proteins contribute to RNA-chaperone activity by binding nonspecifically to large RNA substrates and flexibly tethering the core for the unwinding of neighboring duplexes.

    View details for DOI 10.1073/pnas.1109566108

    View details for Web of Science ID 000293129900019

    View details for PubMedID 21746911

  • DEAD-box proteins as RNA helicases and chaperones WILEY INTERDISCIPLINARY REVIEWS-RNA Jarmoskaite, I., Russell, R. 2011; 2 (1): 135-152

    Abstract

    DEAD-box proteins are ubiquitous in RNA-mediated processes and function by coupling cycles of ATP binding and hydrolysis to changes in affinity for single-stranded RNA. Many DEAD-box proteins use this basic mechanism as the foundation for a version of RNA helicase activity, efficiently separating the strands of short RNA duplexes in a process that involves little or no translocation. This activity, coupled with mechanisms to direct different DEAD-box proteins to their physiological substrates, allows them to promote RNA folding steps and rearrangements and to accelerate remodeling of RNA?protein complexes. This review will describe the properties of DEAD-box proteins as RNA helicases and the current understanding of how the energy from ATPase activity is used to drive the separation of RNA duplex strands. It will then describe how the basic biochemical properties allow some DEAD-box proteins to function as chaperones by promoting RNA folding reactions, with a focus on the self-splicing group I and group II intron RNAs.

    View details for DOI 10.1002/wrna.50

    View details for Web of Science ID 000301861900010

    View details for PubMedID 21297876

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