USC researchers peering deep inside a living cell have discovered something surprising: its system for preventing genetic damage from disease can fail so badly that the cell would be better off without it.
This is a paradoxical finding because it challenges the idea that tiny keepers of cell division proteins always provide protection, but research shows that they can sometimes allow bad things to happen just by doing their work too well.
The results have important implications for the treatment of cancer. In addition, glitches in DNA replication lead to other genetic diseases, including birth defects, autism and neurological disorders. The capacity of a cell to create new cells is also important for maintaining tissues and organs.
“In general, cells respond to errors during DNA replication by deploying monitoring proteins, called checkpoints, which are used to recognize the problem and stop cell division to prevent damage to the chromosomes” said Susan Forsburg, lead author of the study and professor emeritus of Biology at USC Dornsife College of Letters, Arts and Sciences. “This study makes the unexpected finding that in some forms of replication stress, an active checkpoint actually allows the cells to divide, causing more serious damage than if it were missing completely.”
The results appear in a scientific article published today in the journal Molecular and cellular biology.
Study of the consequences of this lack of DNA replication
This is fondamental research in how cells work, how they divide to form new cells, and how the integrated molecular checks and balances ensure that cell division occurs properly. It’s the kind of foundation on which clinicians and translational scientists can find better ways to treat disease.
“We are interested in how problems with DNA replication lead to bad things for cells and people, including cancer,” said Forsburg.
For the study, the scientists used a type of yeast – Schizosaccharomyces pombe – with chromosomes similar to those in humans and which uses the same genes to maintain these chromosomes. It has proven to be an important model for cell division.
“The analogy I use compares a Mercedes and a lawn mower,” said Forsburg. “If you’re trying to understand the basics of an internal combustion engine, the lawn mower is a simplified version of the Mercedes engine. Yeast uses the same genes as we do, and every gene we study has a human equivalent, with almost all of them linked to cancer. “
In the study, the scientists looked at the cells’ response to a defect overseen by an important gene called CDS1. It functions as a guardian of the DNA replication process and has an analog in humans called CHEK1. As a checkpoint, the gene ensures that DNA is copied smoothly before cell division. Usually when something is wrong and prevents DNA replication, the gene prevents cells from dividing until they can solve the problem. Otherwise, cells would divide without properly replicated DNA, which has fatal consequences.
Cancer treatments often combine drugs that hinder DNA replication with compounds that block the checkpoint, such as a poison pill to cause tumor cells to die deadly. This study finds a condition where this poisoned pill backfires.
“We found that the active checkpoint actually allowed the cells to divide abnormally,” said Forsburg. “Unexpectedly, when we removed the replication checkpoint, the mutant cells did not divide because another damage control mechanism intervened to stop unwanted cell divisions.”
Study will lead to better understanding of cells and better cancer treatments
How can a gene that seeks to maintain cell health degrade so badly that it perpetuates damage to tissue or organs? In some cases, it appears that the checkpoint is blind and continues to do its job when it would be best to take time off.
Forsburg explained: “Our experiments looked at a very specific defect in DNA replication, and it looks like it created a perfect storm. The checkpoint didn’t know what to do with it. Its best effort to protect the cells actually allowed them to slip into deadly divisions. “
The results help advance understanding of the inner workings of cells and how cancer treatments can be improved. This year, approximately 1.8 million new cases of cancer will be diagnosed and 606,520 Cancer deaths will occur in the United States, according to the American Cancer Society.
Seong Min Kim et al. The active replication checkpoint leads to genome instability in the fission yeast mutant mcm4, Molecular and cellular biology (2020). DOI: 10.1128 / MCB.00033-20
University of Southern California
Quote: Scientists examine the impact of a very specific defect in DNA replication (2020, June 29) recovered on June 29, 2020 at https://phys.org/news/2020-06-scientists-impact- specific-defect-dna.html
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