Cell and Developmental Biology Commons^™

Effect Of S100b Deletion On Membrane Properties And Localization Of Ncald And Hpca, Natasha Hesketh

Graduate School of Biomedical Sciences Theses and Dissertations

Calcium signaling is particularly important for neuronal function. Neurons utilize a wide range of calcium-binding proteins. Dysregulation of such proteins is linked to neurodegeneration. Neurocalcin delta (NCALD), hippocalcin (HPCA), and S100B are calcium sensors that are expressed in the hippocampus, a brain region essential to memory and severely damaged in Alzheimer’s disease (AD). Despite the potential importance of these proteins, we do not fully understand the physiological significance of their relationship. Because NCALD and HPCA are known to interact with S100B, we hypothesized that the loss of S100B affects NCALD and HPCA localization, and therefore electrical properties, of hippocampal neurons. …

The Autoimmune System: The Effect Of Physiological Stressors On Autoantibody Glycosylation And Fidelity Of Autoantibody Profiles, Rahil Kheirkhah

Graduate School of Biomedical Sciences Theses and Dissertations

The presence of thousands of autoantibodies (aABs) in the human sera is typical, and therefore it is possible to identify an aAB profile for each individual. In the first part of this thesis, we will show the cerebrospinal fluid also exhibits an extraordinarily complex immunoglobulin G aAB profile that is composed of thousands of aABs. We show that the pattern of expression of individual aABs in CSF closely mimics that in the blood, indicative of a blood-based origin for CSF aABs. In addition, using longitudinal serum samples obtained over a span of nine years, we show remarkable stability in aAB …

Histidine-Triad Hydrolases Provide Resistance To Peptide-Nucleotide Antibiotics., Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like …

Elucidation Of The Mechanisms By Which Anesthetics Induce Blood-Brain Barrier Breakdown And Delirium In The Elderly, George A. Godsey Ii

Graduate School of Biomedical Sciences Theses and Dissertations

Delirium is a highly prevalent neuropsychiatric or neurocognitive disorder that presents a major problem to modern healthcare. Patients suffering from delirium normally have a worse prognosis, prolonged hospital stay, increased hospital cost, long-term cognitive impairment, and higher mortality rates. Many factors can predispose one to develop delirium, which makes treating this disorder a daunting task. Unfortunately, delirium is the most common psychiatric syndrome found in the hospital setting. In fact, a form of delirium known as postoperative delirium (POD) is one of the most common postoperative complications faced by elderly patients undergoing surgery.

POD is a major problem in modern …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

A High Throughput Assay For The Detection Of Stimulator Of Interferon Genes (Sting) Agonists, Michael J. Ingling

Graduate School of Biomedical Sciences Theses and Dissertations

The innate immune system includes a menagerie of different cell types, each with a different role in the process of monitoring the body for invaders and presenting gathered debris (antigen) to the adaptive immune system. Somatic cells have intracellular receptors for the same purpose. Cancer cells, however, have avoided these methods of detection despite, in many cases, the tumor’s immunogenic traits. Immuno-oncology is a field dedicated to the immunological traits of tumors, more recently finding ways of instigating an immune response against tumors. In this regard, STING, a receptor of cyclic dinucleotides (CDN), has come to the forefront of immuno-oncology. …

Characterization Of Human Dutpase, Shawna Marie Rotoli

Graduate School of Biomedical Sciences Theses and Dissertations

Deoxyuridine nucleotidyl transferase (dUTPase) is an enzyme found in all organisms that have thymine as a component of DNA. It catalyzes the hydrolysis of dUTP to dUMP and pyrophosphate thus precluding the buildup of dUTP pools as well as providing the substrate, dUMP, for the de novo synthesis of thymidylate. In Homo sapiens, there are four isoforms: mitochondrial (mDut), nuclear (nDut), variant 3 and variant 4. This work is largely focused on nDut. Using structural and MS analyses of recombinant dUTPase constructs, an intermolecular disulfide bridge between cysteine-3 of each nDut monomer was discovered. It was found that these two …

The Yeast Protein Mam33 Functions In The Assembly Of The Mitochondrial Ribosome, Gabrielle A Hillman, Michael F Henry

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mitochondrial ribosomes are functionally specialized for the synthesis of several essential inner membrane proteins of the respiratory chain. Although remarkable progress has been made toward understanding the structure of mitoribosomes, the pathways and factors that facilitate their biogenesis remain largely unknown. The long unstructured domains of unassembled ribosomal proteins are highly prone to misfolding and often require dedicated chaperones to prevent aggregation. To date, chaperones that ensure safe delivery to the assembling ribosome have not been identified in the mitochondrion. In this study, a respiratory synthetic lethality screen revealed a role for an evolutionarily conserved mitochondrial matrix protein called Mam33 …

The Effect Of Intracellular Zinc Levels In Escherichia Coli On Metallo-Β-Lactamase Activity, Jill Thompson

Graduate School of Biomedical Sciences Theses and Dissertations

Antibiotic resistance is a consequence of evolution via natural selection and poses a serious threat to the world's population. Escherichia coli, and other bacterial species, have acquired genes encoding Metallo-β-Lactamases (MBLs). MBLs are zinc-dependent enzymes that degrade most β-lactam antibiotics, and have emerged as important antibacterial resistance determinants in multidrug resistant pathogens. There are several different families of MBLs, and the major clinically relevant ones are Verona Integrated-encoded Metallo-β-Lactamases (VIMs), Imipenemases (IMPs), and New Delhi Metallo-β-Lactamases (NDMs). These enzymes confer high level resistance to penicillins, cephalosporins, and carbapenems, and are not inhibited by FDA-approved β-lactamase inhibitors. Variants of NDM have …

Yfmk Is A Novel Nε-Lysine Acetyltransferase That Directly Acetylates The Histone-Like Protein Hbsu In Bacillus Subtilis, Valerie J. Carabetta, Todd M. Greco, Ileana M. Cristea, David Dubnau

Rowan-Virtua Research Day

Recently, N^e-lysine acetylation was realized to be a prevalent bacterial post-translational modification (PTM), contrary to the historical notion that this was a rare occurrence. Acetylation can impact protein function in multiple ways, by modifying conformation, interactions, subcellular localization or activity. In bacteria, hundreds of proteins are known to be acetylated, including those involved essential processes such as DNA replication, nucleoid organization, translation, cell shape, central carbon metabolism, and even several virulence factors. Despite the growing recognition that numerous proteins are acetylated, the biological significance of the vast majority of these modifications in any bacteria remains largely unknown. Previously, …

Times Of Action And Evolutionary Conservation Of Heterochronic Genes, Maria Ivanova, Eric G. Moss

Rowan-Virtua Research Day

Specific genes called heterochronic genes control the timing and sequence of developmental events during larval stages of C. elegans. Mutations in heterochronic genes can cause skipping or reiteration of cell fates associated with certain larval stages. lin-14 and lin-28 are two well-studied heterochronic genes. LIN-14 acts during the first larval stage (L1) and controls events of the L1 and L2 stages, LIN-28 acts during the L2 stage and controls its events.

A Dedicated Chaperone Mediates The Safe Transfer Of Mitoribosomal Proteins To Their Site Of Assembly, Gabrielle Ashley Hillman

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondrial ribosomes are functionally specialized for the synthesis of several essential inner membrane proteins of the respiratory chain. While remarkable progress has recently been made towards understanding the structure of mitoribosomes, the unique pathways and factors that facilitate their biogenesis remain largely unknown. This dissertation defines the physiological role of an evolutionarily conserved yeast protein called Mam33 in mitochondrial ribosome assembly. The biomedical relevance of this finding stems from the fact that mutations or changes in its expression of the human ortholog p32 result in mitochondrial dysfunction. In human patients, bi-allelic mutations cause severe multisystemic defects in mitochondrial energy metabolism, …

Cyclin C: The Story Of A Non-Cycling Cyclin, Jan Jezek, Daniel G J Smethurst, David C Stieg, Z A C Kiss, Sara E Hanley, Vidyaramanan Ganesan, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The class I cyclin family is a well-studied group of structurally conserved proteins that interact with their associated cyclin-dependent kinases (Cdks) to regulate different stages of cell cycle progression depending on their oscillating expression levels. However, the role of class II cyclins, which primarily act as transcription factors and whose expression remains constant throughout the cell cycle, is less well understood. As a classic example of a transcriptional cyclin, cyclin C forms a regulatory sub-complex with its partner kinase Cdk8 and two accessory subunits Med12 and Med13 called the Cdk8-dependent kinase module (CKM). The CKM reversibly associates with the multi-subunit …

Cysteine Residues Contribute To The Dimerization And Enzymatic Activity Of Human Nuclear Dutp Nucleotidohydrolase (Ndut)., Shawna M Rotoli, Julia L Jones, Salvatore J Caradonna

Rowan-Virtua School of Osteopathic Medicine Departmental Research

dUTPase is an enzyme found in all organisms that have thymine as a constituent of DNA. Through evolution, humans have two major isoforms of dUTPase: a mitochondrial (mDut) and a nuclear (nDut) isoform. The nuclear isoform of dUTPase is a 164-amino-acids-long protein containing three cysteine residues. nDut's starting methionine is post-translationally cleaved, leaving four unique amino acids on its amino-terminus including one cysteine residue (C3). These are not present in the mitochondrial isoform (mDut). Using mass spectrometry analyses of recombinant dUTPase constructs, we have discovered an intermolecular disulfide bridge between cysteine-3 of each nDut monomer. We have found that these …

Iron-Dependent Cleavage Of Ribosomal Rna During Oxidative Stress In The Yeast Saccharomyces Cerevisiae, Jessica A Zinskie, Arnab Ghosh, Brandon M Trainor, Daniel Shedlovskiy, Dimitri G Pestov, Natalia Shcherbik

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well-understood. Here we show that a chemical rather than an enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5Δ cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate …

Escherichia Coli Itat Is A Type Ii Toxin That Inhibits Translation By Acetylating Isoleucyl-Trnaile, Brendan Wilcox, Ilya Osterman, Marina Serebryakova, Dmitry Lukyanov, Ekaterina Komarova, Bridget Gollan, Natalia Morozova, Yuri I Wolf, Kira S Makarova, Sophie Helaine, Petr Sergiev, Svetlana Dubiley, Sergei Borukhov, Konstantin Severinov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Prokaryotic toxin-antitoxin (TA) modules are highly abundant and are involved in stress response and drug tolerance. The most common type II TA modules consist of two interacting proteins. The type II toxins are diverse enzymes targeting various essential intracellular targets. The antitoxin binds to cognate toxin and inhibits its function. Recently, TA modules whose toxins are GNAT-family acetyltransferases were described. For two such systems, the target of acetylation was shown to be aminoacyl-tRNA: the TacT toxin targets aminoacylated elongator tRNAs, while AtaT targets the amino acid moiety of initiating tRNAMet. We show that the itaRT gene pair from Escherichia coli …

N-Terminal Domain Of Human Uracil Dna Glycosylase (Hung2) Promotes Targeting To Uracil Sites Adjacent To Ssdna-Dsdna Junctions, Brian P Weiser, Gaddiel Rodriguez, Philip A Cole, James T Stivers

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The N-terminal domain (NTD) of nuclear human uracil DNA glycosylase (hUNG2) assists in targeting hUNG2 to replication forks through specific interactions with replication protein A (RPA). Here, we explored hUNG2 activity in the presence and absence of RPA using substrates with ssDNA-dsDNA junctions that mimic structural features of the replication fork and transcriptional R-loops. We find that when RPA is tightly bound to the ssDNA overhang of junction DNA substrates, base excision by hUNG2 is strongly biased toward uracils located 21 bp or less from the ssDNA-dsDNA junction. In the absence of RPA, hUNG2 still showed an 8-fold excision bias …

The Role Of Developmental Timing Regulators In Progenitor Proliferation And Cell Fate Specification During Mammalian Neurogenesis, Jennifer S. Romer-Seibert

Graduate School of Biomedical Sciences Theses and Dissertations

Developmental timing is a key aspect of tissue and organ formation in which distinct cell types are generated through a series of steps from common progenitors. These progenitors undergo specific changes in gene expression that signifies both a distinct progenitor type and developmental time point that thereby specifies a particular cell fate at that stage of development. The nervous system is an important setting for understanding developmental timing because different cell types are produced in a certain order and the switch from stem cells to progenitors requires precise timing and regulation. Notable examples of such regulatory molecules include the RNA-binding …

Inhibition Of Ribosome Biogenesis Through Genetic And Chemical Approaches, Leonid Anikin

Graduate School of Biomedical Sciences Theses and Dissertations

In order to maintain the ability to generate proteins, proliferating cells must continuously generate ribosomes, designating up to 80% of their energy to ribosome biogenesis (RBG). RBG involves transcription of rDNA by RNA polymerases I (Pol I) and III (Pol III), expression of approximately 80 ribosomal proteins, and assembly of these components in a process referred to as ribosome maturation. During maturation, the Pol I transcribed 47S pre-rRNA undergoes a number of processing events, while simultaneously interacting with processing factors and ribosomal proteins that drive pre-ribosome assembly. Inhibition of RBG has become one of the pursued targets for cancer therapy …

Insight Into Translational Activation In Yeast Mitochondria, Julia Lynn Jones

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondrial function depends on over a thousand proteins, of which the majority are nuclear DNA-encoded and approximately one percent are mitochondrial DNA-encoded. The mitochondrial DNA of Saccharomyces cerevisiae contains eight protein-encoding genes, seven of which are required for proper function of the respiratory complexes and one encodes a ribosomal protein. The bigenomic nature of the oxidative phosphorylation complexes requires coordinated expression and regulation from both the nuclear and the mitochondrial genomes. It is currently unclear how this regulatory network operates. However, it is thought that nuclear genome-encoded messengers localized to the mitochondria aid in this coordination.

A family of proteins …

Loss Of Marv1 Promotes Chop Signaling In Mouse Liver, Shad Anthony Mitchell

Graduate School of Biomedical Sciences Theses and Dissertations

Metabolic syndrome (MetS) is a term used to define a set of metabolic diseases: obesity, type 2 diabetes (T2D), hyperlipidemia, hypertension, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic hepatosteatosis (NASH). Those with MetS have a higher incidence of cardiovascular disease and stroke. Current drug treatments for MetS treat the individual pathologies associated with the diseases, rather than directly targeting MetS as a whole. We hypothesize that the inhibition of a ubiquitous lipid transporter known as ARV1 can improve pathologies associated with MetS. To test this hypothesis, we utilized liver tissue from mARV1 knockout mice fed a high-fat diet and examined …

Snf1 Cooperates With The Cwi Mapk Pathway To Mediate The Degradation Of Med13 Following Oxidative Stress, Stephen D Willis, David C Stieg, Kai Li Ong, Ravina Shah, Alexandra K. Strich, Julianne H Grose, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Eukaryotic cells, when faced with unfavorable environmental conditions, mount either pro-survival or pro-death programs. The conserved cyclin C-Cdk8 kinase plays a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core Mediator complex of RNA polymerase II. In Saccharomyces cerevisiae, oxidative stress triggers Med13 destruction, which releases cyclin C into the cytoplasm to promote mitochondrial fission and programmed cell death. The SCFGrr1 ubiquitin ligase mediates Med13 degradation dependent on the cell wall integrity pathway, MAPK Slt2. Here we show that the AMP kinase Snf1 activates a second …

The Zinc Transporter Zipt-7.1 Regulates Sperm Activation In Nematodes, Yanmei Zhao, Chieh-Hsiang Tan, Amber Krauchunas, Andrea Scharf, Nicholas Dietrich, Kurt Warnhoff, Zhiheng Yuan, Marina Druzhinina, Sam Guoping Gu, Long Miao, Andrew Singson, Ronald E Ellis, Kerry Kornfeld

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Sperm activation is a fascinating example of cell differentiation, in which immotile spermatids undergo a rapid and dramatic transition to become mature, motile sperm. Because the sperm nucleus is transcriptionally silent, this transition does not involve transcriptional changes. Although Caenorhabditis elegans is a leading model for studies of sperm activation, the mechanisms by which signaling pathways induce this transformation remain poorly characterized. Here we show that a conserved transmembrane zinc transporter, ZIPT-7.1, regulates the induction of sperm activation in Caenorhabditis nematodes. The zipt-7.1 mutant hermaphrodites cannot self-fertilize, and males reproduce poorly, because mutant spermatids are defective in responding to activating …

Acetic Acid Induces Sch9p-Dependent Translocation Of Isc1p From The Endoplasmic Reticulum Into Mitochondria, António Rego, Katrina F Cooper, Justin Snider, Yusuf A Hannun, Vítor Costa, Manuela Côrte-Real, Susana R Chaves

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Changes in sphingolipid metabolism have been linked to modulation of cell fate in both yeast and mammalian cells. We previously assessed the role of sphingolipids in cell death regulation using a well characterized yeast model of acetic acid-induced regulated cell death, finding that Isc1p, inositol phosphosphingolipid phospholipase C, plays a pro-death role in this process. Indeed, isc1∆ mutants exhibited a higher resistance to acetic acid associated with reduced mitochondrial alterations. Here, we show that Isc1p is regulated by Sch9p under acetic acid stress, since both single and double mutants lacking Isc1p or/and Sch9p have the same resistant phenotype, and SCH9 …

Till Death Do Us Part: The Marriage Of Autophagy And Apoptosis., Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Autophagy is a widely conserved catabolic process that is necessary for maintaining cellular homeostasis under normal physiological conditions and driving the cell to switch back to this status quo under times of starvation, hypoxia, and oxidative stress. The potential similarities and differences between basal autophagy and stimulus-induced autophagy are still largely unknown. Both act by clearing aberrant or unnecessary cytoplasmic material, such as misfolded proteins, supernumerary and defective organelles. The relationship between reactive oxygen species (ROS) and autophagy is complex. Cellular ROS is predominantly derived from mitochondria. Autophagy is triggered by this event, and by clearing the defective organelles effectively, …

A Complex Molecular Switch Directs Stress-Induced Cyclin C Nuclear Release Through Scfgrr1-Mediated Degradation Of Med13., David C Stieg, Stephen D Willis, Vidyaramanan Ganesan, Kai Li Ong, Joseph Scuorzo, Mia Song, Julianne Grose, Randy Strich, Katrina F Cooper

Rowan-Virtua School of Osteopathic Medicine Departmental Research

In response to oxidative stress, cells decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module, which, with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In

Guidelines And Recommendations On Yeast Cell Death Nomenclature, Didac Carmona-Gutierrez, Maria Anna Bauer, Andreas Zimmermann, Andrés Aguilera, Nicanor Austriaco, Kathryn Ayscough, Rena Balzan, Shoshana Bar-Nun, Antonio Barrientos, Peter Belenky, Marc Blondel, Ralf J Braun, Michael Breitenbach, William C Burhans, Sabrina Büttner, Duccio Cavalieri, Michael Chang, Katrina F Cooper, Manuela Côrte-Real, Vítor Costa, Christophe Cullin, Ian Dawes, Jörn Dengjel, Martin B Dickman, Tobias Eisenberg, Birthe Fahrenkrog, Nicolas Fasel, Kai-Uwe Fröhlich, Ali Gargouri, Sergio Giannattasio, Paola Goffrini, Campbell W Gourlay, Chris M Grant, Michael T Greenwood, Nicoletta Guaragnella, Thomas Heger, Jürgen Heinisch, Eva Herker, Johannes M Herrmann, Sebastian Hofer, Antonio Jiménez-Ruiz, Helmut Jungwirth, Katharina Kainz, Dimitrios P Kontoyiannis, Paula Ludovico, Stéphen Manon, Enzo Martegani, Cristina Mazzoni, Lynn A Megeney, Chris Meisinger, Jens Nielsen, Thomas Nyström, Heinz D Osiewacz, Tiago F Outeiro, Hay-Oak Park, Tobias Pendl, Dina Petranovic, Stephane Picot, Peter Polčic, Ted Powers, Mark Ramsdale, Mark Rinnerthaler, Patrick Rockenfeller, Christoph Ruckenstuhl, Raffael Schaffrath, Maria Segovia, Fedor F Severin, Amir Sharon, Stephan J Sigrist, Cornelia Sommer-Ruck, Maria João Sousa, Johan M Thevelein, Karin Thevissen, Vladimir Titorenko, Michel B Toledano, Mick Tuite, F-Nora Vögtle, Benedikt Westermann, Joris Winderickx, Silke Wissing, Stefan Wölfl, Zhaojie J Zhang, Richard Y Zhao, Bing Zhou, Lorenzo Galluzzi, Guido Kroemer, Frank Madeo

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic …

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

Modification Of The Ribosome As Part Of The Adaptive Response To Oxidative Stress In Yeast, Jessica A Zinskie, Daniel Shedlovskiy, Ethan Gardner, Dimitri G Pestov, Natalia Shcherbik

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Living organisms are constantly exposed to a variety of environmental and internal stressors tha tare detrimental to their cellular physiology and viability. One such condition, oxidativestress, is caused by abnormal amounts of Reactive Oxygen Species (ROS) that can lead to damage to proteins, nucleic acids, and lipids. Although the mechanisms to neutralize ROS have been widely studied, the understanding of ROS‐mediated signaling for these mechanisms is rather incomplete and sparse. We have uncovered a previously undescribed phenomenon of yeast ribosomes to respond to elevated levels of ROS through a specific endonucleolytic cleavage of the 25S rRNA in the c‐loop of …

Targeting Ribosome Assembly Factors Selectively Protects P53 Positive Cells From Chemotherapeutic Agents, Russell T. Sapio, Anastasiya Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, N. Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Many chemotherapeutic agents act in a nondiscriminatory fashion, targeting both cancerous and noncancerous cells in Sphase and Mphase. One approach to reduce the toxic side effects in normal tissue is to exploit the differences in p53 functionality between cancerous and noncancerous cells. For example, activating p53 signaling by nongenotoxic means can transiently arrest noncancerous p53 positive cells in G1 phase and protect them from the cytotoxic effects of chemotherapeutic drugs. However, since most cancerous cells have faulty p53 signaling, they will proceed to cycle, and continue to be affected by the drug. In this study we asked if this G1‐phase …