Splitsville

How cells divide, in sickness and in health

Life as we know it is based on cell division, the elegant and equal divvying up of one cell’s contents—DNA, cytoplasm and organelles—between its two daughter cells.

The correct division of DNA between the two cells, known as mitosis, is vital to this process. If a cell receives too many chromosomes or too few, it will probably die or become cancerous.

Terry Orr-Weaver and Iain Cheeseman study how cells break apart and reassemble DNA during cell division. Photos: John Soares

Two Whitehead Members, Terry Orr-Weaver and Iain Cheeseman, study this astonishing, beautiful and sometimes perilous process.

Orr-Weaver’s lab focuses on which genes and proteins are important in DNA replication in the mother cell and which are important in the division of chromosomes between the daughter cells. She uses the fruit fly, which her work has shown is a powerful model for cell division in humans. “The genes and proteins involved in cell division seem to be almost the same in fruit flies and humans,” says Orr-Weaver.

The Cheeseman lab examines the role of the kinetochore, a group of proteins required for cell division and chromosome segregation. “You have this huge complex molecular structure that attaches to both the DNA and the microtubules, which are proteins that are changing all the time—always growing and shrinking, creating the force for dividing the chromosomes,” says Cheeseman. “Those interfaces are fascinating.” His lab also investigates the individual molecular machines that make up this structure.

Mitosis research has much to say about cancer, which is all about cell division gone wrong. Some existing cancer drugs target mitosis, taking advantage of cancer cells’ high cell division rate to impede tumor growth.

Here are glimpses of the six stages of the cell cycle, with notes on some research under way.

Images: Iain Cheeseman

Interphase

For most of its life, a cell is in “interphase.” During this time, the cell obtains nutrients, grows and performs its other cellular duties. The cell also prepares for mitosis by copying its DNA, which is isolated in the nucleus from the rest of the cell and appears like a blob in the cell’s center.

In this human cell beginning to divide, the DNA is stained blue, the microtubules are stained green, and the key protein “handles” known as kinetochores are stained red.

Such images have long been familiar to scientists. Since the early 1880s, researchers have used light microscopes to watch DNA divide during mitosis. Although advancements in microscopy, including special stains and the ability to record moving images, allowed scientists to peer at the details of this phenomenon, research was still confined to the visible.

But with the explosion of research at the genetic and molecular level that began in the 1980s, scientists have dug much deeper into mitosis, analyzing the interplay of proteins that make it possible.

Prophase

Through a microscope, a complex organism’s DNA at the beginning of mitosis looks like a bowl of tangled, thick noodles in the cell’s nucleus.

Although the nucleus seems like a chaotic mess, it is highly organized. Each noodle is two sister chromatids—tightly compressed, identical copies of one of the original cell’s chromosomes. The sisters are tightly held together with the protein cohesin, which acts like stiff rubber bands all along the noodle. A cohesin complex of proteins at the centromere, a region near the middle of the chromatids, acts as a super strong band.

As mitosis progresses, most of the cohesin along the chromatids’ arms is released, with the cohesin complex at the centromere still helping to hold the sister chromatids together.

In 1995, Terry Orr-Weaver’s lab identified a key protein in fruit flies that is involved in meiosis (a type of cell division that takes place only in cells destined to become eggs, sperm or spores). This protein, MEI-S332, sits on the centromere and protects the cohesin complex as long as it holds things together. Nine years later, a lab in Japan found a protein in yeast similar to MEI-S332. Other researchers started finding proteins like MEI-S332 in many organisms, including humans. Dubbed “shugoshin” (Japanese for “guardian spirit”), the proteins all protect the cohesin complex. In humans, shugoshin is required for mitosis.

Prometaphase

As mitosis continues, the membrane around the nucleus dissolves. Microtubules—thin, strong filaments of protein—grab the DNA. The microtubules are the ropes that pull the sister chromatids apart.

In humans, these microtubules are anchored at either end of the cell. From these anchor points, microtubules extend toward the noodley tangle of DNA. The microtubules hook onto a protein complex called the kinetochore, which is attached to each sister chromatid’s centromere. If a microtubule misses a kinetochore, it retracts and starts over. This process continues until each kinetochore grips a microtubule. Then the pulling begins.

A decade ago, only 10 of the currently known 80-100 kinetochore proteins had been identified. Iain Cheeseman’s work as a graduate student and postdoc helped contribute to a large increase in the kinetochore’s molecular parts list. “It’s an amazingly complex, intricate structure, and once you know what the components are, you can start to figure out how it all works,” says Cheeseman.

Since his postdoctoral research, Cheeseman has worked on a group of kinetochore proteins involved in gripping the microtubule. “Not only does the group physically connect to the microtubule, it has to hold onto these polymers that are growing or shrinking like mad all of the time, to ultimately provide the force to move the chromosomes.”

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