A literally ‘sweet’ discovery was recently put forth by scientists at Johns Hopkins. Researchers reveal that with the help of an elaborate sleuthing system they developed, they could probe how cells seem to manage their own division. It came to light that common yet difficult-to-see sugar switches may probably be partly in control.
Scientists are of the opinion that this discovery may have implications for new treatments. This could be mainly due to the abundance of these previously unrecognized sugar switches and could be potential targets of manipulation by drugs. It should help in many treatments for a wide range of diseases inclusive of cancer.
Reportedly the team centered their attention and efforts on the apparatus that allowed a human cell to split into two. It was described as a complex biochemical machine that seemingly involving hundreds of proteins. The team revealed something much unlike conventional wisdom that until now inferred phosphates and chemical compounds containing the element phosphorus to hold the job of turning these proteins on and off thus determining if, how and when a cell divides.
The Johns Hopkins scientists instead claimed that another layer of regulation by a process of sugar-based protein modification named O-GlcNAcylation (pronounced O-glick-NAC-alation) could be present.
This sugar-based system seems as influential and ubiquitous a cell-division signaling pathway as its phosphate counterpart and, indeed, even plays a role in regulating phosphorylation itself,” mentions Chad Slawson, Ph.D., an author of the paper and research associate in the Department of Biological Chemistry, Johns Hopkins University School of Medicine.
Apparently the innovative qualities of the sugar molecule, researchers employing standard physical techniques of detection such as mass spectrometry may find it to virtually imperceptible. Some attributes of the molecule include small dimensions, easily alterable and without an electric charge. Suspicion of sugar known as O-GlcNAc to play a part in cell division led the team to devise a protein-mapping scheme that took advantage of new mass spectrometric methods. The scientists revealed to have applied a combination of methods that included chemical modification and enrichment along with novel fragmentation technology.
These were applied to proteins that included the cell division machinery which could probably help figure out and analyze their molecular makeup. Identifying more than 150 sites where O-GlcNAc was attached, phosphates they found were apparently attached at more than 300 sites. The researchers observed that the O-GlcNAc molecule located near a phosphate site, or at the same site prevented the phosphate from attaching. Until O-GlcNAc detached, the proteins engaged in cell division were not phosphorylated and activated.
“I think of phosphorylation as a micro-switch that regulates the circuitry of cell division, and O-GlcNAcylation as the safety switch that regulates the microswitches,” remarks Gerald Hart, Ph.D., the DeLamar Professor and director of biological chemistry at the Johns Hopkins School of Medicine.
The use of a standard human cell line (HeLa cells) further allowed the scientists to uncover abnormalities when they disturbed the cell division process by addition of an extra O-GlcNAc. Though the cell’s chromosome-containing nuclei was found to divide normally, it was observed that the cells themselves didn’t divide. This appeared to have resulted in innumerable nuclei per cell. The condition known as polyploidy is apparently displayed by many cancer cells.
“As important as the discovery is to a deeper understanding of cell division,” Hart shares, “This extensive cross talk between O-GlcNAc and phosphorylation is paradigm-shifting in terms of signaling. Signaling is how a cell perceives its environment, and how it regulates its machinery in response to stimuli. The new sugar switches reveal that the cellular circuitry is much more complex than previously thought.”
Moreover, the researchers not only mapped O-GlcNAc and phosphorylation sites but also determined alterations in the cell division machinery. As per Hart, the chemical changes seem to function more like ‘dimmer’ switches, than simple on/off ones.
The findings appeared in the January 12 edition ofScience Signaling.