Enzyme discovery sheds light on causes of rare disease, cancer

September 14, 2003

Discovery of a new enzyme, PHF9, is providing insight into the biological processes involved in development of Fanconi anemia (FA), a rare genetic disorder that primarily affects children. The detection of the enzyme enhances understanding of the common DNA repair pathways involved in FA, as well as certain cancers and aging, scientists say. Better understanding of these pathways could lead to new therapies for Fanconi anemia.

Scientists at the National Institute on Aging (NIA) found that genetic mutations in an important protein complex inactivate PHF9. This disrupts critical intracellular repair mechanisms and leads to many serious complications associated with FA including the inability to make red blood cells.

"FA is a disease that appears to be the result of breakdowns in DNA repair mechanisms, which are important for all of us," said Weidong Wang, Ph.D., an investigator in the NIA's Laboratory of Genetics. "Some scientists theorize that DNA damage, which gradually accumulates as we age, leads to malfunctioning genes and deteriorating tissues and organs as well as increased risks of cancer as years go by. So every time we learn something more about DNA repair, we can hope to use that new knowledge to find ways to prevent the excessive damage to DNA that appears to occur with aging."

The finding is scheduled for advanced online publication in the journal, Nature Genetics (http://www.nature.com/ng/), during the week of September 14, 2003. The report also will be published in journal's October 2003 print edition.

Dr. Wang and his colleagues detected PHF9 and its corresponding gene while attempting to verify the existence of the Fanconi protein complex and identify its structure. Based on earlier work, the researchers suspected that the complex incorporated proteins produced by at least five previously known FA genes. Today's findings not only confirm that the complex exists, they also for the first time describe its composition, which includes nearly all of the proteins produced by the previously known FA genes plus PHF9 and several other new proteins.

The FA complex normally promotes a cascade of changes in a biochemical pathway that ultimately leads to the repair of cellular DNA damage. But if any of the proteins within the complex--including PHF9 itself--are mutated, the enzyme is disabled and the DNA repair pathway is disrupted. As a result, the person develops FA. Other researchers have found that similar disruptions in this DNA repair pathway can contribute to the development of ovarian, pancreatic, and other cancers in people who aren't at risk for FA. This suggests that PHF9 is a potent cog within the DNA repair machinery, Dr.Wang said.

"What makes the discovery of PHF9 particularly important is that none of the previously known FA gene products are enzymes," Dr.Wang said. "So the PHF9 enzyme is the key. All of the other proteins in this complex function through it. If you think of the FA complex as a factory, PHF9 is the machine that creates the product. Without it, the complex makes nothing."

Fanconi anemia, named for Swiss pediatrician, Guido Fanconi, affects about 1 in every 300,000 children. If both parents have the same mutation in the same FA gene, each of their children has a one-in-four chance of inheriting the defective gene from both parents and developing FA or certain types of cancer.

The disease leads to bone marrow failure (aplastic anemia) and is associated with birth defects such as missing or extra thumbs and skeletal abnormalities of the hips, spine or ribs. Many who have FA eventually develop acute myelogenous leukemia and are prone to head and neck, gastrointestinal and other cancers. The first symptoms, such as nose bleeds or easy bruising, usually begin before age 12. In rare instances, however, symptoms do not become apparent until adulthood.

The Nature Genetics report represents a hopeful new area of scientific inquiry for those who have the disease and their families, said David Frohnmayer, president of the University of Oregon in Eugene and a spokesman for the Fanconi Anemia Research Fund, www.fanconi.org. He and his wife, Lynn, helped incorporate the Fund in 1989. Two of their daughters have died of complications from the disease.

"Anything that can be found to further explain the FA complex and its functions is extremely important not only for the people who suffer from this disorder, but for the world of scientific discovery at the molecular level generally and especially those interested in DNA repair and cancer," Frohnmayer said. "This is the kind of discovery that takes a rare orphan disease and puts it in the mainstream of important science that affects the lives of millions of people."

In addition to NIA, researchers at the Baylor College of Medicine in Houston, the Oregon Health & Science University in Portland, and the Free University Medical Center in Amsterdam, The Netherlands, contributed to this work.
-end-
The NIA is one of 27 Institutes and Centers of the National Institutes of Health in the U.S. Department of Health and Human Services. The NIA leads Federal efforts to support and conduct basic, clinical, epidemiological, and social research on aging and the special needs of older people. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information web site, www.nia.nih.gov.

NIH/National Institute on Aging

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.