USC Dornsife scientists examine the impact of a very specific defect in DNA replication
USC researchers peering deep inside a living cell have discovered something surprising: Its system for preventing genetic damage linked to diseases can fail so badly that the cell would be better off without it.
It’s a paradoxical finding because it challenges the idea that tiny protein guardians of cell division always offer protection, yet the study shows that they can at times allow bad things to happen simply by doing their job too well.
The findings have important implications for treating cancer. In addition, glitches in DNA replication lead to other genetic diseases, including birth defects, autism and neurological impairments. A cell’s ability to make new cells is also important to sustain tissues and organs.
“Generally, cells respond to errors during DNA replication by deploying monitoring proteins, called checkpoints, that serve to recognize the problem and stop cell division so that chromosome damage is prevented,” said Susan Forsburg, Distinguished Professor of Biological Sciences at the USC Dornsife College of Letters, Arts and Sciences and senior author of the study. “This study makes the unexpected finding that in certain forms of replication stress, an active checkpoint actually allows cells to divide, causing worse damage than if it were missing entirely.”
The findings appear on the cover of the July issue of the journal Molecular and Cellular Biology.
Improved cancer treatments
How can a gene that seeks to help keep the cell healthy mess up so badly that it perpetuates harm to the tissue or organ? In certain instances, it seems the checkpoint gets blindsided and continues doing its job when it would be better if it took the day off.
Forsburg explained: “Our experiments examined a very specific defect in DNA replication, and it appears that this 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 lethal divisions.”
The findings help advance understanding of the inner workings of cells and how cancer treatments can be improved.
About the study
The study authors are Forsburg and Seong Min Kim at USC Dornsife. The work was supported by a National Institutes of Health grant (R35-GM118109).