Messenger RNA With FLASH

A study from the University of North Carolina at Chapel Hill has identified a key player in a molecular process essential for DNA replication within cells.

The new findings highlight a protein called FLASH, already shown to play a role in initiating apoptosis, or programmed cell death. Apoptosis is a normal biochemical response that occurs when a cell is damaged beyond repair after viral infection or accumulation of mutations that could lead to uncontrolled cellular proliferation, or cancer. Apoptosis is also crucial to the developing embryo through selective cell death, which allows proper differentiation of physical structures, such as fingers and toes.

According to senior study author Zbigniew Dominski, Ph.D., associate professor of biochemistry and biophysics at UNC, the new study demonstrates that FLASH is also required for the proper synthesis of histone messenger RNA, which gives rise to histone proteins.

Histones are the chief protein components of chromatin and act as a scaffold allowing packaging of DNA into a condensed form that fits inside the nucleus of a cell. As the DNA interacts with histones and with metabolic signals from within the cell, these proteins help regulate gene expression.

"Our study suggests for the first time that a potential link exists between the processes of histone messenger RNA formation and apoptosis," Dominski said. "FLASH is crucial for the production of histone messenger RNA, without which the cell can't make the histone proteins around which DNA is packaged."

The research is described in the Oct. 23, 2009 issue of the journal Molecular Cell.

For the study, Dominski adapted a laboratory system that reproduces in the test tube what normally occurs in the cell when FLASH participates in the biochemical cleavage event that results in mature histone messenger RNA. This enabled his team to explore what might occur when FLASH was added or removed.

"We could then figure out exactly what portion of FLASH would restore the protein's function in generating histone mRNAs and remarkably, only the first 100 or so amino acids are required. The remaining 2,000 amino acids of this large protein likely control other processes in the cell, including apoptosis and DNA replication," he explained.

Co-author William F. Marzluff, Ph.D., is distinguished professor of biochemistry and biophysics and executive associate dean for basic research in the UNC School of Medicine. He noted that FLASH is the first component found in this protein complex "that integrates or initiates many cellular functions DNA replication, apoptosis, histone production. Having this small piece of the puzzle makes it a lot easier to identify others."

Other UNC coauthors include Xiao-cui Yang, laboratory technician, and Yan Yan, undergraduate student, both from the Department of Biochemistry and Biophysics and the UNC Program in Molecular Biology and Biotechnology and Brandon D. Burch, graduate student in in genetics and molecular biology.

Funding for the study came from the National Institute of General and Medical Sciences, a component of the National Institutes of Health.

Source: University of North Carolina

New Molecules Created By University Of California Riverside Chemists Have Wide Applications

Researchers at the University of California, Riverside have successfully created in the laboratory a class of carbenes, highly reactive molecules, used to make catalysts - substances that facilitate chemical reactions. Until now, chemists believed these carbenes, called "abnormal N-heterocyclic carbenes" or aNHCs, were impossible to make.

Carbenes are made up of unusual carbon atoms and are usually unstable in nature. They attach themselves to metals to form metal-carbene complexes that serve as efficient catalysts used widely in the pharmaceutical industry.

The metal-carbene complexes are formed in two ways: (a) the complex is created in one step, without first preparing carbene independently, and (b) a metal and an independent carbene are brought together to make the complex.

Most often the metal used in a metal-carbene complex is rhodium, gold, platinum or palladium - all of which are very expensive and, in some cases, even toxic. To bring down the cost of catalysts, when possible, carbenes are used independently (without metals) in many chemical reactions.

Until now, aNHCs have been used as only metal-carbene complexes, never independently. Chemists had assumed that aNHCs cannot exist freely, which made them impossible to make.

Now UC Riverside's Guy Bertrand, a distinguished professor of chemistry, and colleagues have challenged that assumption by successfully creating aNHCs that are metal-free and can be used to make any desired complex.

"Many chemical species are believed to be unstable because they do not obey the rules we learned at school, and consequently nobody tries to make them," said Bertrand, who led the research project. "The role of scientists, however, is to challenge former hypotheses. That is just what we did in the case of the aNHCs, and we were successful.

"The aNHCs are stable at room temperature both in the solid state and in solution, which means their application as metal-free catalysts is extremely wide, greatly benefiting industry by making possible scores of new chemical reactions."

Results of the study appear in the Oct. 23 issue of Science.

"This study, reporting the synthesis and characterization of an entirely different class of metal-free NHCs, could open new horizons and have a huge impact on the field of catalysis," said John Schwab, who oversees organic synthesis grants at the National Institutes of Health's National Institute of General Medical Sciences. "The potential applications to drug discovery and manufacture are exciting, since catalytic processes can help keep costs in check and be environmentally friendly, to boot."

Bertrand is interested in making aNHCs commercially available. "We hope many chemists in the world will use these carbenes and find some new applications," he said.

The UCR Office of Technology Commercialization has filed a patent application on the technology and is currently seeking partners in industry interested in developing the technology commercially.

An internationally renowned scientist, Bertrand came to UCR in 2001 from France's national research agency, the Centre National de la Recherche Scientifique (CNRS). He is the director of the UCR-CNRS Joint Research Chemistry Laboratory.

A recipient of numerous awards and honors, most recently he won the 2009-2010 Sir Ronald Nyholm Prize for his seminal research on the chemistry of phosphorus-phosphorus bonds and the chemistry of stable carbenes and their complexes.

He is a recipient of the Japanese Society for Promotion of Science Award, the French-German Humboldt Award, and the International Council on Main Group Chemistry Award. He is a fellow of the American Association for the Advancement of Sciences, and a member of the French Academy of Sciences, the European Academy of Sciences, Academia Europea, and Academies des Technologies.

He has authored more than 300 scholarly papers and holds 35 patents.

Bertrand was joined in the research by Eugenia Aldeco-Perez, Amos J. Rosenthal, and Bruno Donnadieu of UCR; and Gernot Frenking and Pattiyil Parameswaran of Phillips-Universitat Marburg, Germany.

The research project was funded by the National Institutes of Health. The National Council for Science and Technology (CONACYT), Mexico, provided Aldeco-Perez, the first author of the research paper, with financial support.

Source:
Iqbal Pittalwala
University of California - Riverside