How cells prevent extra harmful DNA from being copied – ScienceDaily


According to a new study by Weill Cornell Medicine researchers, a protein that prepares DNA for replication prevents the replication process from spinning out of control. The work was published on January 5 in molecular cellsolves a puzzle that has puzzled biologists for a long time.

Cells of humans and all other higher organisms use a complex system of checkpoints and “licensing” proteins to ensure that they accurately copy their genomes once before dividing. In preparation for cell division, licensing proteins attach to specific regions in DNA, naming them as the origin of replication. When the DNA-synthetic phase of the cell cycle begins, replication begins only at those authorized sites, and only starts, or ‘goes off’ once, according to the current model.

But this model was missing a crucial point. “The same factor that allows this licensing to occur only deteriorates after these replication origins are released,” said senior author Dr. Tobias Meyer, Joseph Hennessy Professor of Cell Biology and Development at Weill Cornell Medicine. “In principle, a cell can load these licensing machines onto DNA that’s already been copied, so, instead of two copies, it gets three or four copies of that piece of DNA, and those cells are expected to lose genome integrity and die or become cancerous.”

Figuring out how cells avoid this fate has been challenging. “We needed to study events in the first minutes of the DNA synthesis phase of the cell cycle, so it’s a very fleeting period,” said first author Nalin Ratnayeke, a graduate student who worked on this project at both Stanford and Weill. Cornell Medicine in Dr. Meyer’s lab. The lab moved to Weill Cornell Medicine in 2020. To solve this challenging experimental problem, Ratnaecki used computer-assisted microscopy to observe thousands of developing cells simultaneously, capturing proliferating cells in the act and analyzing the activities of licensing and replication factors.

The work revealed that the well-known licensing factor CDT1 not only allows a segment of DNA to become a parent for replication, but also acts as a brake on DNA replication, preventing an essential replication enzyme called CMG Helicase from functioning. To begin DNA synthesis, the cell’s enzymes must first break down CDT1. “Previously proposed mechanisms orchestrating this transition from the licensing phase of the cell cycle to the firing phase of the cell cycle relied on inhibitory licensing factors,” Ratnaecki said, adding that “the mechanism we identified here is actually the opposite… The licensing factor CDT1 itself inhibits the progression of acid synthesis Nuclear.

To confirm their findings, the scientists collaborated with colleagues at the Medical Research Council in Cambridge, UK, who found that the inhibitory mechanism could be recapitulated in a simplified system that reproduces the entire DNA synthesis process with purified components in a test tube. said Dr. Meyer, who is also a professor of biochemistry and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Because failures in replication licensing can kill cells or make them cancerous, the findings provide a new understanding of cell health and disease. “Future work to determine what happens mechanistically with Cdt1 inhibition will give biophysical insight into how the CMG helicase works, and will identify specific regions of this complex that can be targeted with drugs,” said Ratnaecki.



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