Cell Biology, Structural Biology
The University of Texas Southwestern Medical Center
Dr. Yu is also a professor of pharmacology at the University of Texas Southwestern Medical Center.
Cellular Mechanisms Governing Chromosome Inheritance and Integrity
Cell biologist Hongtao Yu has learned it's important to expect the unexpected—and exploit it.
"Unexpected things can open new directions for research," he says. That observation has guided his research on the forces that determine chromosome behavior during cell division. Yu's team has found two forms of a protein, Mad2, that make sure each cell gets the correct number of chromosomes during cell division. That finding has opened the way to understanding critical steps—and missteps—in this fundamental activity in all human cells.
The importance of Mad2 is hard to overstate, says Yu, a cell biologist at the University of Texas Southwestern Medical Center. During the dance of the chromosomes that leads to cell division, the mother cell has to make sure each daughter cell is born with the proper number of chromosomes. If not, the result can be a disaster: death or a devastating congenital disease. The Mad2 protein holds up cell division until each chromosome is properly assembled.
Yu's research has revealed that the Mad2 protein molecule can fold into two forms; one of those forms is more active—and more effective. The switch between these two forms is important for proper chromosome partitioning into the two daughters. "We never expected to find this protein can fold into two forms; we didn't expect this surprise," he added. The protein's shape-shifting nature created an added challenge as Yu attempted to capture the molecule, map its structure, and determine how that structure influences its function. But the research provided an important "Aha!" moment that helped steer his research.
Yu arrived at cell biology through an equally circuitous path. He comes from a scientific family—his mother was a chemist and his father an engineer—and he was naturally inclined toward a career in science. He intended to study physics at Peking University, but physics and math were the most popular majors in China, and competition for university seats was fierce. So he chose chemistry instead. "I got interested in the structure of molecules," he says.
When he graduated in 1990, Yu went to the lab of HHMI investigator Stuart Schreiber at Harvard University to study the structure of organic molecules and proteins, in particular. But he soon found that wasn't enough. "Looking at structure and not function is pretty limiting," he noted. "So that's how I got interested in cell biology." He then completed postdoctoral training with cell biologist Marc Kirschner at Harvard Medical School.
In addition to studying chromosome inheritance, Yu's lab also examines how cells repair damage in DNA, especially damage that can cause health problems, such as cancer. He suspects that the way chromosomes form and interact with one another has a profound impact on this repair.
This is just part of an ambitious plan Yu will tackle as an HHMI investigator. "What we're trying to do is to understand the chromosome system at every level, from the cellular level to the protein level and down to the atomic level," he says.
The task will mean marshaling methods from many different disciplines. For example, he and his lab will use microscopy to observe where parts of the cell are and where they go during cell division, biochemistry to describe interactions among the parts of the cell, and biophysics to get snapshots of these proteins at the atomic level. Yu hopes to expand his lab's work to a new area that examines the chemical marks that signify which of a cell's genes are to be expressed, a field called epigenetics. He also wants to do more research on chromatin, which packages and protects the DNA inside a cell.
Yu wants to develop a complete description of the mechanisms that regulate cells when they divide. Breaking down cell division into its parts can help explain what happens during each step and which proteins are the key players. "We hope to learn how to make models of what's happening inside the living cell, looking at various parts of the cell, such as the chromosomes," Yu says. "We want to know everything we can about this basic building block of life, the cell. What makes it tick?"