Corporate Banner
Satellite Banner
RNAi
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Cancer Drug Unties Knots in the Chromosome that Causes Angelman and Prader-Willi Syndromes

Published: Thursday, August 08, 2013
Last Updated: Thursday, August 08, 2013
Bookmark and Share
Researchers have identified how and where in the genome a cancer chemotherapy agent acts on and ‘un-silences’ the epigenetically silenced gene that causes Angelman syndrome.

The agent, Topotecan, is a topoisomerase inhibitor, part of a class of drugs that in earlier research has been found to un-silence the Angelman gene, suggesting that it might be therapeutic for the condition, which affects approximately 1 in 25,000, or approximately 150,000 people worldwide. But how it acts has not been known.

Topotecan is primarily used to treat metastatic cancers, including ovarian cancer, cervical cancer and small-cell lung cancer, by preventing cells from dividing and causing their death.

The research, published online today in Proceedings of the National Academy of Sciences (PNAS), found that the drug stabilizes the formation of strands of RNA that create RNA-DNA hybrids called ‘R-loops,’ in the Ube3a region of the gene15q11-q13. The gene is implicated in other neurodevelopmental disorders, including autism. About 1 percent of cases of autism are linked to duplications in 15q11-q13 or “Dup15q,” children that over-express Ube3a.

The research was conducted using molecular genetic approaches in neural cells from a genetically engineered mouse model and in cell lines containing inserted mouse and human genetic sequences.

“Now we have a molecular mechanism for a proposed drug for a disease, so we can understand how it works and begin to tweak it to develop therapies,” said lead study author Weston Powell, a third-year medical student in the Physician Scientist Training Program in the UC Davis School of Medicine.

Angelman syndrome is caused by the loss of a maternally inherited Ube3a gene at the 15q11-q13 locus, which is expressed in brain neurons. Loss of the same chromosomal region inherited from the male parent causes another neurodevelopmental condition, Prader-Willi syndrome, best known for its sufferers’ obsessive-compulsive behavior and insatiable appetites which, if left unchecked, can lead to morbid obesity.

DNA is like a twisted rope, Powell explained, which opens as the enzyme polymerase travels down one thread of the rope to produce an RNA copy of the DNA strand. Normally the RNA leaves the DNA, but sometimes the RNA instead sticks to one piece of DNA, and an ‘R-loop’ is formed. These hybridized DNA-RNA loops create tension, preventing the DNA from having the characteristic flexibility that allows it to form its spiral helix or twisted-rope shape. R-loops themselves are a relatively recent discovery, and researchers have just begun to understand how they function.

While the discovery of the effect of Topotecan is important, future investigations will determine how and whether the drug may have therapeutic applications for Angelman syndrome, the researchers said.

Janine LaSalle, a basic science MIND Institute researcher, and Weston Powell, a third-year medical student who works with Dr. LaSalle in her lab.

“Topotecan also has an effect everywhere in the genome,” Powell said. “One of the things it does is prevent cells from dividing. That’s why it’s a cancer drug. But that’s also a problem if you want to treat children, because it kills dividing cells.”

Powell said that additional investigations are needed to determine whether the drug can be tweaked to eliminate the global effect and only treat the targeted region.

Senior study author Janine LaSalle, professor of microbiology and immunology and a researcher affiliated with the UC Davis MIND Institute, said that the study highlights the significance of epigenetics in understanding both rare and more common neurodevelopmental disorders.

“What determines whether you have Prader-Willi syndrome or Angelman syndrome is whether the maternal or paternal gene is missing,” LaSalle said. “These are the classic, textbook epigenetic disorders involving parental imprinting. It’s not just about the chromosomes, but it's where — or who — they come from. In our study, we show that R-loops forming on the active paternal chromosome within the Prader-Willi region regulate imprinting of the Angelman gene, Ube3a, on the maternal chromosome.

“Epigenetics is the layers that are put on top of the genetic code by the environment. In the case of the imprinted inheritance of these two diseases, it’s simply the environment of whether the chromosomes travel through the egg or the sperm. But environmental influences, such as diet and exposure to pollutants, also affect the epigenetic layers and are becoming increasingly important in more common disorders such as autism,” La Salle said.

LaSalle said that the finding also is important because the diseases are caused by defects in a common chromosomal locus for autism-spectrum disorders. Rearrangements in 15q are increasing, she said, in both non-human primates and people. Her lab has recently found an association between polychlorinated biphenyl (PCB) levels and 15q rearrangements in human postmortem brain tissue. Future investigations will examine the role of current persistent organic pollutants, such as polybrominated diphenyl ethers (PBDEs), that may have a role in promoting chromosomal rearrangements and epigenetic alterations in this region.


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.


Scientific News
RNAi Screening Trends
Understand current trends and learn which application areas are expected to gain in popularity over the next few years.
New Weapon in the Fight Against Blood Cancer
This strategy, which uses patients’ own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable.
TOPLESS Plants Provide Clues to Human Molecular Interactions
Scientists at Van Andel Research Institute have revealed an important molecular mechanism in plants that has significant similarities to certain signaling mechanisms in humans, which are closely linked to early embryonic development and to diseases such as cancer.
Toxin from Salmonid Fish has Potential to Treat Cancer
Researchers from the University of Freiburg decode molecular mechanism of fish pathogen.
Scientists Create CRISPR/Cas9 Knock-In Mutations in Human T Cells
In a project spearheaded by investigators at UC San Francisco, scientists have devised a new strategy to precisely modify human T cells using the genome-editing system known as CRISPR/Cas9.
Long-sought Discovery Fills in Missing Details of Cell 'Switchboard'
A biomedical breakthrough reveals never-before-seen details of the human body’s cellular switchboard that regulates sensory and hormonal responses.
Tracking Breast Cancer Before it Grows
A team of scientists led by University of Saskatchewan researcher Saroj Kumar is using cutting-edge Canadian Light Source techniques to screen and treat breast cancer at its earliest changes.
New Mussel-Inspired Surgical Protein Glue
Korean scientists have developed a light-activated, mussel protein-based bioadhesive that works on the same principles as mussels attaching to underwater surfaces and insects maintaining structural balance and flexibility.
Web App Helps Researchers Explore Cancer Genetics
Brown University computer scientists have developed a new interactive tool to help researchers and clinicians explore the genetic underpinnings of cancer.
Researchers Develop Vaccine that Protects Primates Against Ebola
A collaborative team from The University of Texas Medical Branch at Galveston and the National Institutes of Health have developed an inhalable vaccine that protects primates against Ebola.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!