Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Discovery of Biological Energy-Sensing Switch Could Have Broad Implications for Biology and Medicine

Published: Tuesday, October 23, 2012
Last Updated: Tuesday, October 23, 2012
Bookmark and Share
Biochemists at The Scripps Research Institute (TSRI) have discovered a genetic sequence that can alter its host gene’s activity in response to cellular energy levels.

The scientists have found this particular energy-sensing switch in bacterial genes, which could make it a target for a powerful new class of antibiotics. If similar energy-sensing switches are also identified for human genes, they may be useful for treating metabolism-related disorders such as type 2 diabetes and heart disease.

“This discovery adds a new dimension to our understanding of how cells sense and manage their energy levels, which is one of the most important processes in biology,” said the study’s senior author, Martha J. Fedor, a professor the departments of Chemical Physiology and Molecular Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.

The findings are described online ahead of print on October 21, 2012, in the journal Nature Chemical Biology.

A Fuel Sensor

This type of gene-switching sequence is known as a riboswitch because it appears on the strand of ribonucleic acid (RNA) that is first transcribed from a gene’s DNA. Unlike other known riboswitches, which have relatively limited functions, this one acts as a sensor for the basic molecular fuel that powers all living cells and controls many genes.

The newly discovered riboswitch detects a small molecule known as adenosine triphosphate (ATP), the standard unit of chemical energy in all known organisms on our planet. Scientists had thought that cells use only large and relatively complex proteins to sense these all-important energy molecules and adjust cell activities accordingly. No one had found ATP sensors among riboswitches, which can alter cell activity at a more fundamental level—usually by interrupting a gene’s transcription from DNA.

Moreover, previously described riboswitches are relatively simple feedback sensors that affect narrow metabolic pathways. Most of them merely sense and adjust the expression rate of their own host gene. “This is the first riboswitch that is known to be involved in global metabolic regulation,” said Fedor.

In recent years, the Fedor team had found hints that such a riboswitch could exist. Many RNA sequences with possible riboswitch activity had never been characterized, and several riboswitches in bacteria sense molecules that are closely related to ATP. Fedor and a graduate student in her laboratory, Peter Y. Watson, therefore set out to find bacterial riboswitches that could indeed sense ATP.

Caught in the Act

The task was more challenging than it might have seemed. Watson could not simply expose suspected riboswitches to ATP and see which ones stuck best to the energy molecules. ATP is present in high concentrations in cells, and its interactions with its known protein sensors are necessarily fleeting, low-affinity affairs. Interactions with a riboswitch would be expected to look the same. “Such interactions are really too weak to be detected using traditional methods,” Watson said. But he found evidence that an RNA interaction with an ATP-like molecule would occur in a way that allows the brief coupling to be caught in the act—using a burst of ultraviolet radiation, which can create a strong chemical crosslink between two molecules.

In this way, he discovered a stretch of apparent ATP-binding RNA known as the ydaO motif. Watson performed structure-mapping analyses of ydaO to confirm that it binds to ATP and to determine precisely where it binds. Attaching ydaO to a “reporter” gene, he found that in bacterial cells, the reporter gene’s expression level stayed low when ATP levels were normal and rose sharply when ATP levels dropped—as would be expected if ydaO is really an ATP-sensing riboswitch. Even in unaltered cells of a test bacterium, B. subtilis, levels of the genes that normally contain the ydaO motif rose and fell in the same way in response to changing ATP levels.

The ydaO motif occurs in the large subset of bacteria known as gram-positive bacteria. Across these bacterial species, it has been found, to date, on 580 separate genes. “These ydaO-regulated genes encode proteins that have a wide variety of functions, from cell wall metabolism to amino acid transport,” Watson said. “It makes sense that a riboswitch in control of such disparate processes would be responding to a central metabolite such as ATP.”

New Possibilities

The finding has basic scientific importance because it is the first known example of a riboswitch that binds ATP; it is also the first known riboswitch that has such broad regulatory functions. “It opens up the possibility that RNA switches are involved in the general regulation of metabolism,” said Fedor.

The fact that ydaO motifs serve as “off-switches” for key bacterial genes also makes them a potential target for new antibiotics. “Hitting these riboswitches with a small-molecule, ATP-mimicking drug so that they can’t turn on genes that promote bacterial growth and survival could be a viable approach,” said Fedor.

Her laboratory will now search for other ATP-sensing riboswitches in bacteria and in higher organisms, including humans. A human ATP-sensing riboswitch, if targeted appropriately by drugs, might be able to alter cell activity in ways that help treat common metabolic disorders. Type 2 diabetes, which presently affects several hundred million people worldwide, is known to feature the improper regulation of ATP levels in cells.

Funding for the study, “The ydaO motif is an ATP-sensing riboswitch in Bacillus subtilis,” was provided by the Skaggs Institute for Chemical Biology at TSRI.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,500+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

More DNA & Extra Copies of Disease Gene in Alzheimer’s Brain Cells
Scientists at The Scripps Research Institute (TSRI) have found diverse genomic changes in single neurons from the brains of Alzheimer’s patients, pointing to an unexpected factor that may underpin the most common form of the disease.
Tuesday, February 24, 2015
Enzyme Could Help Explain Origins of Life
Mimicking natural evolution in a test tube, scientists at The Scripps Research Institute (TSRI) have devised an enzyme with a unique property that might have been crucial to the origin of life on Earth.
Wednesday, October 29, 2014
Chemists Discover Cancer Drug Candidate Structure
Chemists at The Scripps Research Institute have determined the correct structure of a highly promising anticancer compound approved by the U.S. FDA for clinical trials in cancer patients.
Wednesday, May 21, 2014
Revealing Molecular Secrets Behind the Health Benefits of Wine
Resveratrol has been much in the news as the component of grapes and red wine associated with reducing “bad cholesterol,” heart disease and some types of cancer.
Wednesday, April 30, 2014
Scripps Research Appoints Cancer Biologist
Christoph Rader is appointed as associate professor in the Department of Cancer Biology and the Department of Molecular Therapeutics.
Monday, August 06, 2012
Scripps Research Scientists Create Novel RNA Repair Technology
Discovery could aid search for Huntington’s, Spinocerebellar Ataxia, and Kennedy Disease treatments.
Thursday, January 19, 2012
Understanding the Genetics of Anorexia
If a girl's mother was anorexic, there's a very high chance that she will be, too. In the world of science, odds like this strongly suggest a genetic element to the disease, but the research is only beginning to get off the ground – pushed forward by an interdisciplinary team of scientists at Scripps Research.
Wednesday, January 26, 2011
Scripps Scientists Reveal How Genetic Mutations May Cause Type 1 Diabetes
The new molecular understanding could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.
Monday, May 03, 2010
Team Led by Scripps Research Scientists Develops Technique to Determine Ethnic Origin of Stem Cell Lines
Cells more representative of U.S. and world population could lead to more accurate research and safer, effective therapites.
Monday, January 04, 2010
Scripps Scientists Uncover Mimicry at the Molecular Level that Protects Genome Integrity
Study draws new parallels between the Rad60 DNA repair factor and SUMO; both essential for maintaining genome stability during replication.
Wednesday, April 15, 2009
Scripps Research Crystal Structure Reveals Mystery behind Three Rare Childhood Disorders
Researchers have figured out how it is that tiny mutations in a single gene can produce three strikingly different childhood diseases.
Friday, May 30, 2008
Small RNAs may Play Big Role in Embryonic Stem Cells
A new study led by Scripps researchers could increase understanding of stem cells and advance development of potential therapies.
Saturday, April 12, 2008
Scientific News
Poor Survival Rates in Leukemia Linked to Persistent Genetic Mutations
For patients with an often-deadly form of leukemia, new research suggests that lingering cancer-related mutations – detected after initial treatment with chemotherapy – are associated with an increased risk of relapse and poor survival.
Searching Big Data Faster
Theoretical analysis could expand applications of accelerated searching in biology, other fields.
Growing Hepatitis C in the Lab
Recent discovery allows study of naturally occurring forms of hepatitis C virus (HCV) in the lab.
Inciting an Immune Attack on Cancer Cells
A new minimally invasive vaccine that combines cancer cells and immune-enhancing factors could be used clinically to launch a destructive attack on tumors.
Reprogramming Cancer Cells
Researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.
Genetic Overlapping in Multiple Autoimmune Diseases May Suggest Common Therapies
CHOP genomics expert leads analysis of genetic architecture, with eye on repurposing existing drugs.
Surprising Mechanism Behind Antibiotic-Resistant Bacteria Uncovered
Now, scientists at TSRI have discovered that the important human pathogen Staphylococcus aureus, develops resistance to this drug by “switching on” a previously uncharacterized set of genes.
How DNA ‘Proofreader’ Proteins Pick and Edit Their Reading Material
Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have discovered how two important proofreader proteins know where to look for errors during DNA replication and how they work together to signal the body’s repair mechanism.
Fat in the Family?
Study could lead to therapeutics that boost metabolism.
Tissue Bank Pays Dividends for Brain Cancer Research
Checking what’s in the bank – the Brisbane Breast Bank, that is – has paid dividends for UQ cancer researchers.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!