Every time a cell divides, millions of base pairs in its DNA are duplicated. If errors occur in this transcription process, they can lead to cancer. Fortunately nature has found a pretty reliable control system that keeps cell division on track. And now a team of scientists from the University of California at San Francisco has uncovered how parts of that process¿actually, three parts¿work.
"We eventually demonstrated that not one or two but at least three distinct controls have to be turned off simultaneously for cells to start replicating again," says Joachim Li, senior author of the study, which was published today in Nature. "This is unlikely to happen by accident, so this multilayered protection is virtually fail-safe. That's what you want when there is no room for error."
The replication process is initiated when special proteins called replication factors gather in specific places along the DNA molecules in a cell's nucleus. The scientists knew that enzymes called kinases could somehow halt the process by interacting with other cell proteins through phosphorylation, a reaction that adds a phosphate molecule to a protein. So to learn more about the process, the researchers disabled kinase proteins in yeast cells.
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They found that in normal cells, kinases keep at least three replication proteins, Cdc6, Mcm2-7 and origin recognition complex (ORC), from doing their job and, consequently, the cell from dividing in an uncontrolled manner. Thanks to kinases, Cdc6 is chemically degraded; Mcm2-7 is expelled from the nucleus of the cell; and ORC is deactivated in a process that so far has not been explained. Only when the scientists kept kinases from all three factors did cell replication resume. Still, the cells copied only about 50 percent of their DNA, which the scientists say suggests that there may be even more control mechanisms that stop cell division.
"For the first time, we have a system to clarify just what happens when replication is not controlled," Li says. "The research offers a way to move beyond the theory to actual experimental analysis of how re-replication can disrupt the integrity of genetic inheritance and how the cell responds to this disruption. Eventually, we may learn how to enhance cells' abilities to protect themselves from these disruptions."
