Pol3 mutation disrupts organ growth

November 26, 2007

The cellular mechanism that turns DNA into all of the thousands of proteins that make up a human body is itself both intricate and interesting. A key player in the process--called transcription--is the enzyme RNA polymerase III. Work published online this week in the open-access journal PLoS Biology reports that a mutation of this enzyme prevents cell division, but surprisingly, only affects the development of specific organs. It may also have a therapeutic application against cancer.

A team of researchers led by Dr. Michael Pack, at the University of Pennsylvania, investigated the mutation in RNA polymerase III of the zebrafish, an animal model system that is increasingly being used to study human development and disease. Seventeen different subunits combine to form the RNA polymerase III enzyme in organisms as diverse as yeast, zebrafish, and humans. The mutation they studied, which is called slim jim (because mutant fish are comparatively thin due to developmental differences), affects only one of these subunits. This subtle change is enough to prevent cells from dividing, because with disrupted transcription machinery, a cell is unable to make enough protein to give rise to two daughter cells.

To further study how the slim jim mutation affected the 17 subunit RNA Polymerase III complex, Dr. Pack's laboratory collaborated with Dr. Richard Maraia. Dr. Maraia's laboratory, at the National Institutes of Health, engineered a similar mutation in the fission yeast Sacchromyces pombe. These experiments showed that the mutation's effect arises because the mutated subunit cannot interact properly with one of its neighbors in the yeast RNA Polymerase III complex. Remarkably, Dr. Pack's lab showed that when high levels of this interacting subunit are experimentally induced in zebrafish, the slim jim defects were reversed. These experiments are interesting because they show how highly conserved the transcriptional mechanism and its regulation have been throughout animal evolution.

The slim jim mutation only has a strong effect in certain zebrafish tissues, such as the intestine, whereas other organs, including the heart, are relatively unaffected. Dr. Pack explained that this is likely to derive from the different developmental patterns of each organ. Tissues that require cell division to continue late into development or in the adult--and therefore have higher demands for protein production--are the most severely affected.

This provides hope that disrupting this gene in cancer patients may prove beneficial. Cancer is a disease caused by unstoppable cell division, and a therapy that decreases the efficiency of RNA Polymerase III would have a strong effect specifically on cancer growth, which has very high demands for protein production.
Citation: Yee NS,, Gong W, Huang Y, Lorent K, Dolan AC , et al. (2007) Mutation of RNA Pol III subunit rpc2/polr3b leads to deficiency of subunit Rpc11 and disrupts zebrafish digestive development. PLoS Biol 5(11): 12.doi:10.1371/journal.pbio.0050312

Michael Pack
University of Pennsylvania
Medicine and Cell and Developmental Biology
Philadelphia, PA 19104
+1-215-898-9871 (fax)


All works published in PLoS Biology are open access. Everything is immediately available--to read, download, redistribute, include in databases, and otherwise use--without cost to anyone, anywhere, subject only to the condition that the original authorship and source are properly attributed. Copyright is retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.


Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.