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The stop and go of the cell cycle: Research reveals an important checkpoint

Stanford scientists have discovered the signaling pathway responsible for making sure all DNA is replicated before cell division can occur.

Are you the same person you were last week? Well, mostly, but many of your worn out cells have been replaced with brand new ones.

Different types of cells are regenerated at different rates, but all cells share the same steps involved in replication. Reproducing precisely is important to ensure the new cells operate correctly.

Now, Stanford Medicine scientists have discovered a process that regulates the timing of the cell division cycle -- a quality check of sorts. The molecular pathway prevents cells from dividing before two complete copies of their DNA have been made. The discovery could lead to the development of ways to target and stop replication of cancer cells.

paper describing the findings appears in Science.

"We always suspected that there was something signaling when DNA replication was done, but no one ever knew what that was," said Karlene Cimprich, PhD, professor of chemical and systems biology and senior author of the paper. "We think we have uncovered some of the machinery controlling this signal, giving us insight into this mechanism."

When cells replicate, they undergo a series of steps -- always in the same order. In the first phase, a gap phase called G1, the cell grows and checks that everything is okay for it to divide. The second phase is the S phase, in which DNA is replicated in order to form two sets of chromosomes. In the third phase, another gap phase called G2, other cellular material is replicated. The fourth phase is mitosis, in which the chromosomes are segregated and the cell splits into two.

But how do cells know when it's time to move from one phase to the next? Previous research revealed checkpoints that control the transition from G1 to the S phase and from G2 to mitosis. But until now, the checkpoint between the S phase and G2 was unknown.

"Advances in technology are what has allowed us to discover this particular checkpoint," said Joshua Saldivar, PhD, a postdoctoral scholar in chemical and systems biology and lead author of the study that took more than two years to complete. "It's easy to measure, for example, the G2-M checkpoint because it's easy to see mitosis occur. The same goes for the G1-S checkpoint -- it's easy to visualize DNA synthesis or at least detect it. It's more difficult to detect a gap like G2."

The scientists used drugs that interrupted various biochemical reactions during the different phases of the cell cycle. Automated microscopes took thousands of pictures, about 10,000 images an hour, and specialized software programs analyzed them. "The work is a combination of molecular biology, high-content imaging genetic sequencing and bioinformatic analysis," Cimprich said. "We then just had to be clever about how we looked at the data."

The molecular pathway they discovered, which they refer to as the S/G2 checkpoint, detects ongoing DNA replication and sends out a signal that delays the start of the G2 phase. A series of enzymes relay signals, ultimately leading to the inactivation of a particular kinase that gives the thumbs up to mitosis.

"Essentially, the S phase holds up a stop sign, and keeps holding it up until all of the DNA has been replicated," Cimprich said. "Once the stop sign comes down, a transcription program of 50 or 60 genes switches on that prepares the cell for mitosis."

The researchers hope that this new knowledge concerning cell replication can be used to target the growth of cancer cells.

Photo by knerri61

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