Nav: Home

USC scientists examine the impact of a very specific defect in DNA replication

June 29, 2020

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
The findings appear in a scientific paper published today in the journal
.

Investigating the aftermath of DNA replication problems

This is fundamental research into the principles of how cells operate, how they divide to form new cells and how built-in molecular checks and balances ensure that cell division occurs correctly. It's the sort of foundation upon which clinicians and translational scientists can find better ways to treat diseases.

"We are interested in how problems in DNA replication lead to bad things for cells and people, including cancer," Forsburg said.

For the study, the scientists utilized a type of yeast -- Schizosaccharomyces pombe -- with chromosomes similar to those in humans and that uses the same genes to maintain those chromosomes. It's been proven as an important model for cell division.

"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."

In the study, the scientists examined how cells respond to a defect supervised by an important gene called CDS1. It functions like a guardian for the DNA replication process, and it has an analog in humans called CHEK1. As a checkpoint, the gene ensures the DNA is smoothly copied before cell division. Usually, when something goes wrong that hinders DNA replication, the gene stops cells from dividing until they can fix the problem. Otherwise, cells would divide without properly replicated DNA, which has deadly consequences.

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. This study finds a condition where that poison pill backfires.

"We found that the active checkpoint actually allowed the cells to divide abnormally," Forsburg said. "Unexpectedly, when we deleted the replication checkpoint, the mutant cells didn't divide because another damage control mechanism kicked in to stop the unwanted cell divisions."

Study will lead to better understanding of cells, 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."
-end-
The findings help advance understanding of the inner workings of cells and how cancer treatments can be improved. This year, an estimated 1.8 million new cancer cases will be diagnosed and 606,520 cancer deaths will occur in the United States, according to the

The study authors are Seong Min Kim and Susan L. Forsburg in the Department of Molecular and Computational Biology at USC Dornsife.

The work was supported by a National Institutes of Health grant (R35-GM118109).

University of Southern California

Related Cell Division Articles:

Genetic signature boosts protein production during cell division
A research team has uncovered a genetic signature that enables cells to adapt their protein production according to their state.
Inner 'clockwork' sets the time for cell division in bacteria
Researchers at the Biozentrum of the University of Basel have discovered a 'clockwork' mechanism that controls cell division in bacteria.
Scientists detail how chromosomes reorganize after cell division
Researchers have discovered key mechanisms and structural details of a fundamental biological process--how a cell nucleus and its chromosomal material reorganizes itself after cell division.
Targeting cell division in pancreatic cancer
Study provides new evidence of synergistic effects of drugs that inhibit cell division and support for further clinical trials.
Scientists gain new insights into the mechanisms of cell division
Mitosis is the process by which the genetic information encoded on chromosomes is equally distributed to two daughter cells, a fundamental feature of all life on earth.
Cell division at high speed
When two proteins work together, this worsens the prognosis for lung cancer patients: their chances of survival are particularly poor in this case.
Cell biology: The complexity of division by two
Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have identified a novel protein that plays a crucial role in the formation of the mitotic spindle, which is essential for correct segregation of a full set of chromosomes to each daughter cell during cell division.
Better together: Mitochondrial fusion supports cell division
New research from Washington University in St. Louis shows that when cells divide rapidly, their mitochondria are fused together.
Seeing is believing: Monitoring real time changes during cell division
Scientist have cast new light on the behaviour of tiny hair-like structures called cilia found on almost every cell in the body.
Exhaustive analysis reveals cell division's inner timing mechanisms
After exploring every possible correlation, researchers shed new light on a long-standing question about what triggers cell division.

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Meditations on Loneliness
Original broadcast date: April 24, 2020. We're a social species now living in isolation. But loneliness was a problem well before this era of social distancing. This hour, TED speakers explore how we can live and make peace with loneliness. Guests on the show include author and illustrator Jonny Sun, psychologist Susan Pinker, architect Grace Kim, and writer Suleika Jaouad.
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.