USC researchers studying cell division discovered a specific gene defect that has important implications for treating cancer and other genetic diseases, the university announced Monday.
The lab study took a deep look into the principals of how cells operate and revealed an “unexpected glitch” in a gene that supervises mitosis, a type of cell division typical of ordinary tissue growth, researchers said. They found that a living cell’s system for preventing genetic damage from 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,” according to findings published Monday in the journal Molecular and Cellular Biology.
The study has important implications for treating cancer, researchers said. In addition, glitches in DNA replication lead to other genetic diseases, including birth defects, autism and neurological impairments.
“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, senior author of the study and a distinguished professor of biology at the USC Dornsife College of Letters, Arts and Sciences. “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.”
For the study, scientists utilized a type of yeast — Schizosaccharomyces pombe — with chromosomes similar to those in humans to examine how those cells would respond to a defect supervised by a gene called CDS1. It functions like a guardian for the DNA replication process, and it has an analog in humans called CHEK1.
“The analogy I use is comparing a Mercedes and a lawnmower,” Forsburg said. “If you’re trying to understand the basic principles of an internal combustion engine, the lawnmower is a simplified version of the Mercedes engine. The yeast uses the same genes we do, and every gene we study has a human equivalent, with nearly all of them linked to cancer.”
Cancer treatments often combine drugs that hinder DNA replication with compounds that block the checkpoint, “like a poison pill to drive the tumor cells into a lethal division,” but the study revealed a condition where that poison pill backfires, Forsburg explained.
“We found that the active checkpoint actually allowed the cells to divide abnormally,” she said. “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.”
She said the study, co-authored by Seong Min Kim, helps advance the understanding of the inner workings of cells and how cancer treatments can be improved.