A study of how one protein enzyme, BubR1, helps make sure chromosomes are equally distributed during mitosis might explain how the process of cell division goes so awry in cancer, according to researchers from Fox Chase Cancer Center. Their findings might offer a better understanding of the processes behind cancer-cell survival and drug-resistance.
In an article published online today in the Journal of Cell Biology, the Fox Chase researchers demonstrate that the BubR1 protein contains four separate functional areas that take part in cell division. Mutations in these areas, the researchers say, lead to a genetic rearrangement similar to a process that allows cancer cells to evade destruction by medical treatment. Inhibiting BubR1 could be a strategy that enhances the killing power of current therapeutics, co-author Tim J. Yen, Ph.D., believes.
"Improper chromosomal segregation is a hallmark of cancer – it scrambles chromosomes and shuffles the genetic deck in a way that helps some cancer cells to evade destruction," says Yen, a senior member of the Fox Chase scientific staff. "This shuffling can, in effect, push a cancer cell to evolve in a way that allows it to survive drug or radiation therapy."
According to Yen, cancer cells survive by playing a risky evolutionary gamble. Improper chromosomal segregation allows cancer cells to shuffle their genetic deck to select for traits that allow them to survive and continue to grow. The downside of this strategy is that some daughter cells are dealt bad hands and die. As long as the genetic alterations are made on a relatively small scale, Yen says, cells within the tumor will continually evolve so that they can readily adapt to drugs.
"But here is an opportunity to force cancer's hand, as it were, by causing more damaging changes on a much larger scale than cancer cells can handle," Yen says. "Given that BubR1 is responsible for properly dealing from the genetic deck, its inhibition would result in catastrophic genetic changes that are incompatible with cancer-cell life."
The BubR1 enzyme has multiple roles as part of the cellular machinery that physically moves each of the 23 pairs of human chromosome into each new daughter cell. The pro-tein also plays a part in regulating the so-called mitotic checkpoints, which serve as qual-ity control for cell division. If the machinery does not function properly or the check-points are ignored, some daughter cells get more than their accustomed share of DNA, which can offer them a competitive advantage, Yen says.
Yen and Haomin Huang, Ph.D., a postdoctoral fellow in Yen's laboratory and lead author of the paper, determined that the structure of the BubR1 protein undergoes four chemical modifications that may be important for turning the activity of this enzyme off or on. By mutating BubR1 at positions within the protein that become chemically modified, the re-searchers were able to determine some of the protein's roles in the process of chromosome segregation during mitosis.
One position in particular, labeled S670, was found to be essential in preventing division errors. It serves as a means of connecting chromosomes to the microtubule proteins that pull them into the daughter cells. When the researchers prevented S670 from being properly modified, cell-culture studies showed that the chromosomes failed to be distributed equally between the daughter cells during division.
"Our studies show that of all the proteins and protein complexes associated with cell division, the phosphorylation status of BubR1 is a determining factor in cell-cycle control," Yen says. "Exploiting BubR1's crucial functions may help to increase the efficiency of cancer drugs that disrupt DNA replication, like gemcitabine, or drugs that prevent cell division, like paclitaxel."
Greg Lester | EurekAlert!
The birth of a new protein
20.10.2017 | University of Arizona
Building New Moss Factories
20.10.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Interdisciplinary Research
20.10.2017 | Materials Sciences
20.10.2017 | Earth Sciences