Day 1 :
The RNA Institute, SUNY at Albany, USA
Time : 09:15-09:55
Paul F. Agris created and is the founding Director of The RNA Institute, SUNY at Albany. He is known as a Structural Biochemist and innovator in RNA biology, RNA modification science and applications, and nucleic acid design with modified nucleosides. Agris was a Professor and Head of North Carolina State University’s Biochemistry Department, and founded and led the RNA Society of North Carolina for more than a decade. Previously, he was an Assistant, Associate and full Professor in the Division of Biological Sciences and Department of Medicine at the University of Missouri-Columbia. Agris researches into RNA-based therapeutics against infective disease, drug-resistant HIV and MRSA, have been supported continuously by federal agencies since 1974. He is the author of some 170 peer reviewed articles, a number of reviews, chapters and editor of three volumes. Agris founded the RNA-based drug discovery company SIRGA Advanced Biopharma, Inc., Research Triangle Park, NC.
Constantly evolving drug-resistant and multidrug-resistant (MDR) Gram-positive pathogens such as Staphylococcus aureus (methicillin-resistant, MRSA), Streptococcus pneumoniae and Clostridium difficile represent an ever-increasing source of morbidity and mortality in the USA. A new class of topically applied antibiotics against MRSA and other dangerous multi-drug resistant pathogenic infections such as staphylococci and streptococci has been developed. Some bacteria are even developing resistance to vancomycin, an antibiotic drug of last resort. To address these demands, we have selected, screened and characterized a novel putative antibiotic that has little-to-no toxicity, and to which bacteria are slow to develop resistance. This new class of antibiotic targets a ribonucleic acid (RNA) in the cell, rather than a protein. The RNA target is unique to Gram-positive bacteria and is not found in humans, and it is important to basic functions required for the bacteria to live. Our small molecule antibiotic drug turns OFF the RNA function, simultaneously halting expression of as many as 24 genes critical in bacteria, killing the pathogens. Preliminary studies indicate that the new antibiotic is effective against bacteria that had been isolated from humans, is not toxic to human cells in lab cultures at doses effective against bacteria, and is not toxic
in preliminary topical animal studies.
Johns Hopkins University, USA
Keynote: What 40-plus years of study have taught us about the DNA-looping protein AraC and its regulation of the L-arabinose operon in Escherichia coli
Time : 09:55-10:35
Robert Schleif, Professor of Biology and Biophysics, Johns Hopkins University, received graduate training in Physics and Molecular Biology at the University of California, Berkeley, and post doctoral training at Harvard University with Drs. Gilbert and Watson. After 18 years in the Biochemistry Department at Brandeis University, he moved to Johns Hopkins. Current interests are directed towards obtaining a sufficiently deep and detailed understanding of the principles by which AraC functions, that new regulatory proteins utilizing the same principles could be designed and built.
The AraC protein both positively and negatively regulates expression of the L-arabinose operon in Escherichia coli. More than three hundred person-years of research spread over more than four decades has revealed much about gene regulation and transcription factors. This work included the discovery of the phenomenon of DNA looping in gene regulation, and has stimulated development of a number of techniques used in molecular biology including DNA gel retardation assays and missing contact footprinting. The talk will summarize current understanding of the mechanism by which the binding of arabinose to AraC shifts the protein from preferring to loop DNA and repressing the pBAD promoter by binding to two DNA sites separated by 210 base pairs to preferring to bind to two adjacent DNA sites and activating the promoter. Several recent experiments will be described including elucidation of the role of the N-terminal arm of the protein in controlling the protein’s DNA binding properties and experiments demonstrating that arabinose binding to one subunit affects the N-terminal arm of only the opposite subunit.
University of Nebraska Medical Center, USA
Time : 10:35-11:15
Tahir Tahirov has received his Master of Science degree in metallophysics from Kiev Polytechnic Institute (Ukraine). During doctoral training in crystallochemistry in the Chernogolovka branch of the Semenov Institute of Chemical Physics (Russia) he discovered a new class of organic superconductors with two incommensurate crystal lattices. His career in structural biology has started during postdoctoral training in Tsing Hua University (Taiwan) where he solved the first crystal structure of protein. He continued his studies as a researcher at the Himeji Institute of Technology, Osaka University and the Yokohama City University School of Medicine, and then as a team leader at the RIKEN Harima Institute. At the age of 43 Dr. Tahirov became a Full Professor at the Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center. He has published over 120 research articles (50 in physics and chemistry and the rest in structural biology). He is one of the leading experts in structural studies of human DNA replication machinery.
All eukaryotes possess four paralogous B family DNA polymerases: Pola, Pold, Pole and Polz. Pola functions in initiation and early elongation steps of replication. Pola is tightly associated with a primase and hence is the only DNA polymerase that can initiate the synthesis of DNA by extending RNA primers laid by primase. Pold plays a central role in DNA replication and DNA repair in eukaryotic cells. Pole is involved in the initiation of replication at origins and in leading-strand synthesis in the vicinity of the origins, whereas Polz is involved in translesion DNA synthesis. When Pold encounters replication-blocking lesions, it switches from replication to translesion synthesis by recruiting damage bypass polymerases, including Polz. Polz is responsible for nearly all mutations induced by DNA damaging agents in human cells and model organisms. Accumulation of mutations in cellular genetic material causes various diseases, including cancer.In spite of key role of B family DNA polymerases in replication and genome maintenance, only limited data are available regarding mechanisms of their functions. Our aim is to explore the structural features beyond the polymerase catalytic core and reveal how the intersubunit interactions and conformational changes regulate the function of these polymerases. We started with crystal structure-based characterization of the role of the second B-subunits in human B-family DNA polymerases. In particular, we determined the crystal structures of B-subunit complexes for all four DNA polymerases and discovered that Pold and Polz are sharing the same second and third subunits. We will briefly review our recent achievements and focus our presentation on novel crystal structure of entire human primase-Pola complex. The structure reveals how the primase and Pola are acting in a highly coordinated fashion during the initiation of RNA primer synthesis, extension and counting by primase and transfer of primer-template duplex for further extension by Pola.