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Restricting iron can enhance gene silencing

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Holly Korschun

Scientists at Emory University School of Medicine have discovered that drugs that bind dissolved iron, called iron chelators, can enhance RNA interference.

RNA interference refers to both a tool used by researchers to selectively shut off genes in the laboratory, and a process cells use on their own naturally to silence genes.

The finding suggests that iron chelators, which have been tested as possible treatments for cancer, atherosclerosis and neurodegenerative diseases, may be exerting some of their effects by regulating RNA interference. It could also help researchers adapt RNA interference for human medicine.

The results are published in the journal Cell Metabolism.

"Our results say that RNA needs to be taken into account when looking at diseases where iron is playing a role," says senior author Peng Jin, PhD, associate professor of human genetics at Emory University School of Medicine.

The first author of the paper is Yujing Li, a senior associate in Emory's Department of  Human Genetics.

Iron is an essential part of our diets and plays several important roles in our bodies, such as transporting oxygen as part of hemoglobin in red blood cells. Iron deficiency is a common nutritional deficiency and a leading cause of anemia around the world. The reverse situation, having too much iron as a result of conditions such as hemochromatosis or thalassemia, can damage the heart and liver.

Iron is also needed for the synthesis of DNA building blocks. This suggests that fast-growing cancer cells could need iron more acutely than other cells, leading researchers to investigate iron chelators as potential anti-cancer therapy. Similarly, iron is key for the cells' production of reactive oxygen species, and may be important in atherosclerosis and neurodegenerative diseases.

Jin's team's discovery grew out of a search for substances that perturb RNA interference. When researchers introduce RNA into cells artificially, they can hijack machinery inside the cell called the RNA-induced silencing complex.

Li, Jin and their colleagues found that a protein that senses iron levels inside cells, called PCBP2, interacts with Dicer, an essential part of the RNA silencing machinery. This interaction is stronger in the absence of iron.

"Our findings suggest that the iron level inside the cell modulates how much these proteins interact, impacting RNA silencing," Jin says. "These alterations could be making unappreciated contributions to many human diseases where changes in iron are involved."

The research was supported by the National Institutes of Health.

Y. Li, L. Lin, Z. Li, X. Ye, K. Xiong, B. Aryal, Z. Xu, Z. Paroo, Q. Liu, C. He, and P. Jin. Iron homeostasis regulates the activity of the microRNA pathway through poly(C)-binding protein 2. Cell Metab. 15, 1-10. (2012).

National Institute of Neurological Disorders and Stroke (5R01NS051630-07)

National Institute of Mental Health (2R56MH076090-06)

National Institute on Aging (5P50AG025688-08)

Writer: Quinn Eastman

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