Finding Could Pave the Way for New Targets for Antimicrobial Therapy
Newswise — Researchers from NYU Langone Medical Center have discovered and characterized a general mechanism that controls transcription elongation in bacteria. The mechanism, described in the April 23 issue of Science, relies on physical cooperation between a moving ribosome and RNA polymerase (RNAP) that allows for a precise adjustment of the transcriptional yield in response to translational needs. The study could lead to the development of new ways to interfere with bacterial gene expression and serve as a new target for antimicrobial therapy.
“The finding that the active ribosome controls the rate of transcription at every protein-coding gene and under various growth conditions was quite unexpected – and the results are far reaching,” says Evgeny Nudler, PhD, the Julie Wilson Anderson Professor of Biochemistry at NYU Langone Medical Center and lead author of the study. “It appears that the ribosome not just moves behind RNAP while translating the nascent transcript, but it is actually able to ‘push’ the paused or arrested RNAP molecules forward, thereby accelerating RNAP speed and also helping RNAP to traverse road blocks imposed by DNA binding proteins.”
In the study, Nudler and colleagues demonstrate that the rate of transcription elongation perfectly matches the rate of translation under various growth conditions. They also show that the transcription rate depends on codon usage, or the frequency of rare codons which modulates the speed of a ribosome. Finally, the authors illustrate that it is the speed of the ribosome that determines the speed of RNAP -- whereby the acceleration or deceleration of a ribosome by chemical or genetic manipulation leads to corresponding changes in RNAP speed.
Transcription and translation are the two principle events in the pathway of converting the genetic code into proteins. The data shows that these two events are tightly coupled, and cannot proceed efficiently without each other. Thus, uncoupling these processes, by breaking the proposed physical linkage between RNA and polymerase and the ribosome, could be a new way to disrupt bacterial gene expression and serve as a new target for antimicrobial therapy.
The implications of the study are important because it could lead to the development of novel ways to disrupt gene expression and the creation of new antimicrobial therapies. Not only does this cooperation mechanism save energy by limiting any excessive transcripts that cannot be translated in a timely manner, but it also prevents premature transcription termination by Rho factor, ensuring continuous coupling between transcription and translation. Thus, bacteria rely on macromolecule trafficking and cooperation, a fundamentally novel mechanism, to finely control expression of each individual gene in response to nutrient availability and growth phase.Study co-authors also include Sergey Proshkin of the Department of Biochemistry at NYU Langone Medical Center, A. Rachid Rahmouni of the Centre de Biophysique Moleculaire in France and Alexander Mironov at the State Research Institute of Genetics and Selection of Industrial Microorganisms in Russia.
This work was supported by the grants from the National Institutes of Health in Bethesda, Maryland and the Dynasty Foundation in Moscow, Russia.
About NYU Langone Medical CenterNYU Langone Medical Center is one of the nation's premier centers of excellence in healthcare, biomedical research, and medical education. For over 168 years, NYU physicians and researchers have made countless contributions to the practice and science of health care. Today the Medical Center consists of NYU School of Medicine, including the Smilow Research Center, the Skirball Institute of Biomolecular Medicine, and the Sackler Institute of Graduate Biomedical Sciences; and the NYU Hospitals Center, including Tisch Hospital, a 705-bed acute-care general hospital, Rusk Institute of Rehabilitation Medicine, the first and largest facility of its kind, and NYU Hospital for Joint Diseases, a leader in musculoskeletal care, a Clinical Cancer Center and numerous ambulatory sites.
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