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Control of the great divide

Edgar lab finds that well-known fruit-fly protein, E2F1, ensures the fundamental process of cell division proceeds on schedule and error-free
Dr. Bruce Edgar and graduate student Tânia Reis
Dr. Bruce Edgar and graduate student Tânia Reis discovered that the protein E2F1 serves as the factory foreman of the cell cycle. Photo by Todd McNaught

Researchers in the Basic Sciences Division have uncovered a new role for a well-studied fruit-fly protein that explains a decades-old curiosity of the cell-division cycle, the fundamental process of life in which a single cell divides into two.

Scientists have long wondered why the duration of the cell cycle stays constant even when environmental signals cause one part of the cycle to lengthen or shorten. Graduate student Tânia Reis and Dr. Bruce Edgar now have found that a protein called E2F1 serves as a factory foreman of the cell cycle, speeding up or slowing down steps of the assembly-line-like operation so that the cell cycle is completed on time and error-free.

The researchers propose that this master controller — which has counterparts in humans — allows cells to adjust the length of cell-cycle segments in response to signals that accelerate or delay them. Without such regulation, cells may die prematurely or accumulate genetic errors that can lead to cancer.

The findings, which appear in tomorrow's issue of Cell, ultimately could help scientists find new ways to control abnormal cell division and lead to new approaches for treating cancer.

The existence of a compensation system to regulate cell-cycle length first was seen three decades ago, yet a mechanism to explain it has been elusive, Edgar said.

"In yeast cells and human cells grown in laboratory culture, it's been observed that if you perturb the timing of the onset of different parts of the cell cycle, it doesn't hurt the cells or change the length of the cell cycle," he said. "T?nia has uncovered the molecular details of this feedback system."

Reis and Edgar suspect that E2F1 allows the important steps of the cell cycle — a process that occurs thousands of times for a single cell to develop into an animal — to be completed with high fidelity. Their findings may explain why previous studies have found that the mouse version of E2F1 helps to prevent the animal from forming tumors.

Four phases of cell division

Scientists divide the cell cycle into four phases. In S phase, which stands for synthesis, a duplicate copy of each chromosome is made. In M phase, or mitosis, the identical sets of newly duplicated chromosomes are pulled apart and the cell divides into two. The S and M phases are preceded respectively by G1 and G2, "gap" phases in which preparation for DNA duplication and mitosis takes place.

The cycle progresses from one phase to the next through a complex wiring system made up of proteins called cyclins and cyclin-dependent kinases. From previous studies in the lab, Reis said that they knew that E2F1 influenced the timing of production of these proteins.

"We knew that E2F1 regulated many different cell-cycle genes," she said. "But we were both very surprised that it could also be responsible for the cross talk between the phases that leads to the compensation mechanism that we and others have observed."

Researchers in the field typically have approached this problem by speeding up one phase of the cell cycle and observing that the length of another phase lengthens, resulting in no change in overall cell-cycle duration. But Reis and Edgar reasoned that this approach does not distinguish between two possible explanations. One is that the later phase extends simply because it must wait until all the events of an earlier phase are complete. The other possibility is that an active system exists to monitor the duration of each phase and compensate if it notices a timing disturbance.

New experimental approach

Instead of experimentally shortening a phase of the cycle, Reis increased the duration of either the G1 or G2 phase in cells in a part of the developing fly that later becomes the wing. If the first possibility were correct, they would not expect lengthening G1 or G2 to affect the duration of subsequent phases, which would cause the overall length of the cell cycle to increase.

What they observed, though, was that the cell-cycle length stayed the same as in cells in which they did not lengthen G1 or G2. That suggested that the fly cells possess an active system to compensate for the timing disturbance that Reis induced. Given E2F1's known role in cell cycle regulation, Reis tested whether the protein was responsible for the feedback control by repeating the experiment in flies engineered to produce less E2F1. She found that indeed, the compensation system was now lost.

An additional experiment shed light on how the E2F1 system might help protect cells from cancer. Humans and flies contain a protein called Myc that speeds up the cell cycle by accelerating progression from G1 to S. In human cells, overproduction of Myc is associated with many tumors. When Reis overproduced Myc in flies that lacked E2F1, the compensation system failed and the cells died, presumably because they accumulated genetic damage as a result of rushing into S-phase without the requisite supplies of the E2F1 target-gene products needed for efficient DNA replication.

Edgar described E2F1 as a global protection system for the cell. "Our results tell us that timing of the cell cycle is important, and that E2F1 is a fine tuner that helps it to run effectively and to efficiently respond to input without going haywire."

The E2F pathway is present in all animal and plant cells, and a similar system can be found in yeast, Edgar said. Researchers use the term "orthologs" to indicate genes from different species with the same evolutionary origin and function.

"Given that orthologs of the cell-cycle components are found in so many other species, Tânia's results are likely to hold true for other organisms as well."

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