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How cells prevent harmful extra copies of DNA – ScienceDaily

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A protein that prepares DNA for replication also keeps the replication process from getting out of hand, according to a new study by Weill Cornell Medicine researchers. The work, published on January 5 in Molecular cellsolves a mystery that has puzzled biologists for a long time.

Cells in humans and all other higher organisms use a complex system of checkpoints and “licensing” proteins to ensure that they replicate their genome exactly once before dividing. In preparation for cell division, licensing proteins attach to specific regions of DNA, marking them as origins of replication. When the DNA synthesis phase of the cell cycle begins, replication begins only at those licensed sites and is only initiated or “triggered” once, according to the current model.

However, this model was missing an important point. “The very factor that allows this licensing to occur is impaired only after these sources of replication are activated,” said senior author Dr. Tobias Meyer, the Joseph Hinsey Professor of Cell and Developmental Biology at Weill Cornell Medicine. “Basically, a cell could load these licensing machines onto DNA that was already replicating, so instead of two copies, you end up with three or four copies of that segment of DNA, and those cells would be expected to lose their genome integrity and die or get cancer.”

Figuring out how cells avoid this fate has been difficult. “We needed to study events in the first minutes of the DNA synthesis phase of the cell cycle, so this is a very transitional period,” said first author Nalin Ratnajeke, a graduate student who worked on the project at both Stanford University and Weill. Cornell Medicine in Dr. Meyer’s lab. In 2020, the lab moved to Weill Cornell Medicine. To solve this difficult experimental problem, Ratnajeke used automated microscopy to simultaneously monitor thousands of growing cells, capturing replicating cells and analyzing the activity of their licensing and replication factors.

The work showed that a well-known licensing factor, CDT1, not only allows a segment of DNA to become the origin of replication, but also acts as a brake on DNA replication by preventing the function of an essential replication enzyme called CMG helicase. To initiate DNA synthesis, the cell’s enzymes must first cleave CDT1. “Previously proposed mechanisms for coordinating this transition from the licensing phase of the cell cycle to the initiation phase of the cell cycle depended on inhibitory licensing factors,” Ratnaeke said, adding that “the mechanism we identified here is actually the opposite of … the licensing factor CDT1 itself prevents the progress of DNA synthesis.”

To confirm their results, the scientists collaborated with colleagues from the Medical Research Council in Cambridge, UK, who found that the inhibitory mechanism can be summarized in a simplified system that reproduces the entire process of DNA synthesis with purified components in a test tube. “This allowed us to restore all the components for DNA synthesis and prove that the CMG helicase is directly inhibited by CDT1,” said Dr. Meyer, who is also a professor of biochemistry and a member of the Sandra and Edward Meyer Cancer Center. Weill Cornell Medicine.

Because failures in replication licensing can kill cells or make them cancerous, the results provide new insights into cellular health and disease. “Future work to mechanistically determine what happens with Cdt1 inhibition will provide more insight into the biophysics of how the CMG helicase functions and identify specific regions of this complex that can be targeted with drugs,” Ratnaeke said.

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