A study on yeasts encourages rethinking the safeguarding of DNA

DNA replication is more prone to errors in times of stress, leading to mutations that can cause disease.

The cells try to keep their genomes intact. But new research suggests that when resources are scarce, errors begin to slip into the DNA code, which can have catastrophic consequences.

At no time is DNA more vulnerable than when copying during cell division so that it can be shared between the descending cells. To avoid errors when replicating DNA, cells use replay enzymes that copy the code with great fidelity. Or so it was thought.

A new study led by Grant Brown, a professor of biochemistry at Donnelly's Center for Cell and Biomolecular Research at the University of Toronto, suggests that in times of stress, DNA replication errors are much more common than it was thought before. Although researchers have studied yeast cells, a similar process could increase the mutation rate of our own cells, leading to cancer and other diseases.

The results were described in the newspaper Molecular cell.

The discovery took by surprise Brown and David Gallo, a Ph.D. student who did the bulk of the work. They studied the replication of DNA in cells developed with a limited number of nucleotide bases constituting the letters A, T, C and G of the DNA code. "You may think that your car is running out of fuel, we are eliminating gas from DNA replication," says Gallo.

Cells can experience this kind of stress when food is scarce or in case of disease, when resources are depleted by fast-growing cancer cells, for example.

To make a copy of their genome, the cells first unroll the DNA double strand into single strands, where each strand serves as a template against which a new DNA is synthesized by complementary base pairing, A with T and C with G. DNA polymerase enzymes are "extremely accurate and very rarely make mistakes to ensure that the blueprint of life is pbaded on to the next generation with great fidelity," Brown says.

But the lack of building blocks of DNA has caused cells to resort to another type of DNA polymerase, which is more fallible. This was surprising because it was thought that the error-prone polymerases belonged to an activated emergency repair mechanism in response to physical damage, such as DNA damage caused by ultraviolet light or certain carcinogens. And while these enzymes act quickly to copy beyond the damaged part of the DNA, they also make mistakes.

This so-called "mutagenic repair" may seem like a strange way to preserve DNA, but it avoids worse genome destruction scenarios in which unwound DNA strands can cause the loss of chromosome portions.

"It's better to copy and make mistakes than to leave it uncopied and open to chromosomal rearrangements, which would be a lot worse for the cell," says Brown.

The study provides strong evidence for the use of error-prone polymerases when there is no apparent damage to the DNA. This suggests that these polymerases may replicate more DNA than is thought and that this could lead to more mutations that could lead to disease.

If the same is true for human cells, the discovery could have implications for cancer research. Our cells have the same error-prone DNA copy machines. And fast-proliferating cancer cells often experience so-called oncogene-induced replication stress when they run out of fuel, with DNA replication rates exceeding nucleotide supply. Under these conditions, cells could resort to error-prone DNA replication, new mutations that can help cancer survive, although this remains to be verified by future studies.

"The error-prone DNA replication pathway could very well be activated during the stress of oncogene-induced replication to help cancer cells survive," says Gallo. "This would make it a hot therapeutic target to selectively kill cancer cells."

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