The synthesis of proteins is one of the most fundamental processes that makes and sustains us. It’s achieved by the translation of the sequences of messenger RNA (mRNA) to the amino acids that make up all the proteins of the body, and it requires processes that are exquisitely regulated at every step.
The biochemistry textbook dogma for translation goes something like this: the translation machinery comes in contact with and loads onto a strand of mRNA. It then finds a particular sequence called a start codon. Once at the start codon, the machinery begins elongation, or the making of the protein. According to Shu-Bing Qian, Nutritional Sciences, these steps are much more dynamic than once thought. “The more you discover, the more complex it becomes,” Qian says.
Qian’s remarkable discoveries about this process are rewriting the textbook, with vast implications for treating various human diseases. “We’re interested in this process because it eventually determines the quality and quantity of the proteins,” Qian says. “It may be one of the main controls on protein abundance, and it also gives cells sort of an instruction manual for how they are going to cope with a variety of environmental stresses.”
Untangling a Mystery
Qian’s progress in understanding translation began with a groundbreaking tool created in his lab in 2010. The biochemical technique maps the location of the translation machinery as well as the efficiency of that machinery—its output of proteins. This tool has allowed Qian’s lab to study fundamental questions in which they are most interested: How does the translation machinery find the start codon? What are the signals that guide this process?
In answer to these questions, the new tool yielded very quick revisions to the textbook. Previously the relationship between the translation machinery and the start codon, the initiating sequence, would be described as one-to-one. Each unit of translation machinery had to match up with one sequence on the mRNA, one start codon. But in a genome-wide mapping, Qian found that nearly 50 percent of the translation machinery units had more than one option in terms of their start codon choices. How the translation machinery finds the right start codon instantly became more complex.
In subsequent studies, Qian has found that the translation machinery chooses different start codons depending on the state of the cell. If there are plenty of nutrients, for example, the translation machinery will go to its canonical start codon to produce whatever protein is needed to maintain the health of the cell. In the case of nutrient deprivation, however, the same translation machinery will find a different start codon and will make a different protein. And sometimes these proteins will then be degraded and recycled to help the cell survive stress.
“We call this reprogramming,” Qian says. “The cell can reprogram and try to help itself survive.”
A Gateway to Treating Cancer
Another variable in this process is how long the translation machinery takes to begin protein synthesis. At some genes, the machinery pauses before elongation begins. “We actually observed this for a while, but we wondered what the physiological significance of it was,” Qian says. “What does it mean?”
In recent findings, Qian and his students saw that the pause is associated with efficiency—the longer the pause of the translation machinery, the more limited the output or amount of protein produced. Intriguingly, the genes where the machinery pauses the longest seem to be associated with cell growth and proliferation. “These genes seem to have an additional gate control in order to prevent over-production of these proteins,” Qian says.
“It looks like the cancer cancels out and takes advantage of this gate to maximize synthesis. This is quite striking.”
The lab is looking at this gateway in cancer cells, which are known for over-proliferation, and has found that the pausing of the translation machinery at the same genes is gone. “It looks like the cancer cancels out and takes advantage of this gate to maximize synthesis. This is quite striking.”
It had previously been observed that one of cancer’s advantages was in the amount of mRNA loading; cancer promotes more loading of the translation machinery onto more mRNA. But attacking this process to stop the cancer is difficult, as it can’t be distinguished from the loading process of normal cells. “Now we’ve found this additional control that may be more intriguing,” Qian says. “If we can control this gate, we may be able to stop cancer progression.”
As a part of this research, Qian and his team are working to elucidate the signaling that controls the gate and how cancer hijacks it. One answer seems to be certain chemical modifications to the mRNA, namely methylation, the addition of methyl groups, which changes how the translation machinery interacts with even the same sequence of mRNA.
“This modification is very dynamic,” Qian says. In normal cells, Qian has found that the addition of methyl groups works as a kind of roadblock, slowing the translation machinery down. “It looks like in cancer cells, they remove this roadblock, the translation machinery doesn’t pause, and the translation is faster with more final products,” he says.
Qian is currently testing whether or not this gateway can be used to treat cancer in mouse models, with promising results. “This is one example of application of basic research,” Qian says. “I often encourage first-year students to tackle fundamental biology because any discovery in basic science will have the higher impact in applications and clinical settings.”
Understanding the Translation Processes, Relating Them to Diseases
Qian’s lab has many other ongoing projects, and they all address aspects of the translation process at its many stages. “Even before the machinery finds the start codon, there are multiple steps, and we have several projects to try to understand every one,” Qian says.
For example, his lab is working to understand how nutrient signaling initiates translation and how each step in translation is impacted by different kinds of cell stress. He and his students also want to understand the factors that impact how fast or slow the translation machinery scans for start codons.
In their discoveries, the cell’s methods never cease to amaze. With low levels of certain enzymes, for instance, the mRNA will even fold into different configurations to slow the scanning process, which will then direct the translation machinery to one start codon versus another, depending on the needs of the cell.
The dysregulation of any one of these many regulatory processes could be implicated in various diseases, not only in cancer but diabetes and metabolic disorders. “In the very beginning, when I started my lab here at Cornell, we found that nutrient signaling controls the speed of translation, and the higher the speed, the more bad proteins,” Qian says. “This is what happens with lots of metabolic diseases like diabetes; the nutrient signaling stays very high, and lots of junk stuff accumulates and triggers stress, permutation, and then disease.”
A Good Start
In graduate school, Qian studied the opposite process—not protein synthesis but the cell’s degradation of proteins. He became interested in translation when looking at how the cell is able to destroy bad proteins, even as they are being made. “It sounds very paradoxical, but actually it happens all the time in cells,” he says.
As he studied this process, he began to realize how little was known about the mechanisms in translation. “So I have really moved from the death of the protein to the birth,” he says. Qian says there’s so much to be gained for human health by studying this birth—because it’s what happens at the beginning, the foundation. “I always tell my students a good start is half of success. If these processes are working, everything else is easier.”