Public release date: 5-Aug-2013 [ | E-mail | Share ]

Contact: Phyllis Brown phyllis.brown@ucdmc.ucdavis.edu 916-734-9023 University of California - Davis Health System

(SACRAMENTO, Calif.) -- UC Davis 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, a rare neurodevelopmental disorder characterized by severe intellectual disability, seizures, motor impairments, and laughing and smiling.

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.

"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.

Read more here:
How a cancer drug unties knots in the chromosome that causes Angelman and Prader-Willi syndromes

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