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Environmental Factor, August 2012

Research team uncovers a new cellular stress response mechanism

By Melissa Kerr

Peter Dedon, M.D., Ph.D.

Dedon heads an MIT research group whose work addresses the role of RNA secondary modifications in the cellular responses to toxic exposures. He is also a member of the infectious diseases interdisciplinary research group in the Singapore-MIT Alliance for Research and Technology, (http://smart.mit.edu/about-smart/about-smart.html)  which helped fund the study. (Photo courtesy of Peter Dedon)

Thomas Begley, Ph.D.

Asked about the follow up to this study, Begley said that there are more than 35 tRNA modification enzymes in humans, and discovering their roles will bring researchers closer to understanding their functions in signaling and disease. (Photo courtesy of Thomas Begley)

In a recently published study, (http://www.ncbi.nlm.nih.gov/pubmed/22760636)  a team of NIEHS-funded researchers applied innovative technologies to discover a step-wise process in the mechanisms of cell defense against toxic chemicals. They report that when introduced into a stress-inducing environment, the cell attempts to fortify its defenses by modifying a unique program that drives the makeup of its proteins. The findings appeared in the July 3 issue of Nature Communications.

Lead researcher on the team, Peter Dedon, M.D., Ph.D., (http://web.mit.edu/be/people/dedon.shtml)  is a professor of toxicology and biological engineering at the Massachusetts Institute of Technology (MIT). The team included first author Clement Chan, Ph.D., of MIT, and 2006 NIEHS Outstanding New Environmental Scientist awardee Thomas Begley, Ph.D., (http://www.albany.edu/cancergenomics/faculty/tbegley/tbegley.html)  a cancer biologist at the College of Nanoscale Science and Engineering (CNSE) at the University at Albany, along with colleagues from MIT and CNSE.

Dedon and Begley’s research team has focused on RNA mechanisms that control protein expression within a cell. By delineating the mechanisms of cellular response to stress, the team’s research advances understanding of potential targets for attenuating the damaging effects that toxicants and other stressors may have on a cell.

"If you understand the mechanism, then you can design interventions," Dedon explained. “For example, what if we develop ways to block or interrupt the toxic effects of the chronic inflammation?” Inflammation has been implicated in aging and a range of diseases, including cancer.

Protein factory

Proteins are major players within a cell, and the amino acids that make up proteins are specified by the information encoded within a cell’s genes. The process of building proteins, called translation, occurs in the ribosome and consists of transfer ribonucleic acids (tRNA) binding to messenger RNA (mRNA).

Each tRNA carries a particular amino acid, which corresponds to one or more three-base sequences on the mRNA called codons. Other translational enzymes string the amino acids together to make a protein. A key to the research team’s latest work is that different codons for an amino acid are not used equally, with emergency response genes containing biased distributions of specific codons.

Genetic emergency response

The team has now discovered that cells coordinate codon biases in genes with changes in tRNA structure, to adapt the construction of proteins needed for a cell to defend against toxic exposures. Dedon explained, “In the end, a stepwise mechanism leads to selective expression of proteins that you need to survive.”

In earlier work reported in 2010, the team exposed yeast cells to different toxic chemicals, including bleach and hydrogen peroxide, both made by human immune cells. They described a cellular response in which a set of two-dozen tRNA structural modifications reprogram following toxicant exposure. They also found that if the cell did not have the ability to change the tRNA modifications, it would not be able to defend itself. This new study built on those findings by focusing on oxidative stress caused by hydrogen peroxide and a specific tRNA modification called m5C (see text box).

Dedon's and Begley’s team has found that there are particular patterns of tRNA modification that are markers for toxicant exposure and this may match patterns of codon distribution in groups of genes needed to respond to each toxicant. The authors concluded the paper by writing, “The variety of RNA modifications in the tRNA…suggest[s] a mechanism capable of fine tuning the translational response to virtually any cell stimulus.”

The researchers plan to expand their studies of tRNA. If there were some way to control the reprogramming of these tRNA modifications, it could enhance cellular survival. The team also plans to investigate the mechanisms of cancer development in more detail, since certain tRNA-modifying proteins appear to control tumor growth.

Citations:

Chan CT, Dyavaiah M, DeMott MS, Taghizadeh K, Dedon PC, Begley TJ. (http://www.ncbi.nlm.nih.gov/pubmed/21187895)  2010. A quantitative systems approach reveals dynamic control of tRNA modifications during cellular stress. PLoS Genet 6(12):e1001247.

Chan CT, Pang YL, Deng W, Babu IR, Dyavaiah M, Begley TJ, Dedon PC. (http://www.ncbi.nlm.nih.gov/pubmed/22760636)  2012. Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun 3:937.

(Melissa Kerr studies chemistry at North Carolina Central University. She is currently an intern in the NIEHS Office of Communications and Public Liaison.)


Proposed mechanism by which increase in m5C level regulates translation of ribosomal protein paralogues and confers resistance to hydrogen peroxide (H2O2).

Proposed mechanism by which increase in m5C level regulates translation of ribosomal protein paralogues and confers resistance to hydrogen peroxide (H2O2). Exposure to H2O2 leads to an elevation in the level of m5C at the wobble position of the leucine tRNA for translating the codon UUG on mRNA (a), which enhances the translation of the UUG-enriched RPL22A mRNA relative to its paralogue RPL22B (b) and leads to changes in ribosome composition (c). This reprogramming of tRNA and ribosomes ultimately causes selective translation of proteins from genes enriched with the codon TTG (d). (Courtesy of Peter Dedon, this graphic was first published in Nature Communications.)


An emergency response to oxidative stress

The tRNA carries a three-letter genetic code on one end, called the anticodon. These anticodons match with a corresponding codon on the mRNA.

The study by the Dedon-Begley team focuses on a particular tRNA modification called m5C, which is found on the first letter of the anticodon portion of the leucine tRNA that pairs with the TTG codon in genes. The researchers fond that when cells are exposed to hydrogen peroxide, the level of m5C on the tRNA increases, which leads to increased translation of TTG-enriched genes into proteins. This reprogramming of tRNA spurs the cell to change the structure of the protein-assembling ribosome machinery in a way that generates critical proteins to counter the damage produced by hydrogen peroxide.

“You need this sort of emergency ribosome response to make the critical proteins,” Dedon said.



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