Using an elaborate（精心制作的） sleuthing（侦查） system they developed to probe how cells manage their own division, Johns Hopkins scientists have discovered that common but hard-to-see sugar switches are partly in control. Because these previously¹ unrecognized sugar switches are so abundant（充裕的，丰富的） and potential targets of manipulation（操作，处理） by drugs, the discovery of their role has implications for new treatments for a number of diseases, including cancer, the scientists say.

In the January 12 edition of Science Signaling, the team reported that it focused efforts on the apparatus²（装置，设备） that enables a human cell to split into two, a complicated biochemical（生物化学的） machine involving hundreds of proteins. Conventional wisdom was that the job of turning these proteins on and off — thus determining if, how and when a cell divides — fell to phosphates（磷酸盐） , chemical compounds containing the element phosphorus（磷） , which fasten to and unfasten from proteins in a process called phosphorylation（磷脂化作用） .

Instead, the Johns Hopkins scientists say, there is another layer of regulation by a process of sugar-based protein modification³ called O-GlcNAcylation (pronounced O-glick-NAC-alation). "This sugar-based system seems as influential⁴ and ubiquitous（普遍存在的） a cell-division signaling pathway as its phosphate counterpart and, indeed, even plays a role in regulating phosphorylation itself," says Chad Slawson, Ph.D., an author of the paper and research associate in the Department of Biological Chemistry, Johns Hopkins University School of Medicine.

Because the sugar molecule⁵ has some novel qualities — it is small, easily altered, and without an electrical charge — it is virtually imperceptible（感觉不到的，极细微的） to researchers using standard physical techniques of detection such as mass spectrometry（质谱分析法） .

Suspecting that the sugar known as O-GlcNAc might play a role in cell division, the Hopkins team devised a protein-mapping scheme using new mass spectrometric methods. Essentially⁶, they applied⁷ a combination of chemical modification and enrichment methods, and new fragmentation（破碎，分裂） technology to proteins that comprise the cell division machinery⁸ in order to figure out and analyze⁹ their molecular¹⁰ makeup¹¹, identifying more than 150 sites where the sugar molecule known as O-GlcNAc was attached. Phosphates were found to be attached at more than 300 sites.

They noticed that when an O-GlcNAc molecule was located near a phosphate site, or at the same site, it prevented the phosphate from attaching. The proteins involved in cell division weren't phosphorylated and activated¹² until O-GlcNAc detached.

"I think of phosphorylation as a micro-switch that regulates the circuitry（电路系统） of cell division, and O-GlcNAcylation as the safety switch that regulates the microswitches," says Gerald Hart, Ph.D., the DeLamar Professor and director of biological chemistry at the Johns Hopkins School of Medicine.

Using a standard human cell line (HeLa cells), the scientists discovered abnormalities when they disrupted the cell division process by adding extra O-GlcNAc. Although the cell's chromosome-containing nuclei¹³（核心） divided normally, the cells themselves didn't divide, resulting in too many nuclei per cell — a condition known as polyploidy（多倍体） that's exhibited by many cancer cells.

The researchers not only mapped O-GlcNAc and phosphorylation sites but also measured changes in the cell division machinery, because, Hart says, the chemical changes act more like "dimmer（调光器） " switches, than simple on/off ones.

As important as the discovery is to a deeper understanding of cell division, Hart says, 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 stimuli¹⁴（刺激，促进因素） . The new sugar switches reveal that the cellular¹⁵ circuitry is much more complex than previously thought, he adds.