In the lab, Dicer is used in mice to switch off any combination of genes -- either in targeted or in random fashion -- to infer a gene's function, a capability that may be especially useful in understanding cancer and developing improved cancer therapies. Using the enzyme, it may be possible, Doudna explained, to "change silencing in cells to turn off genes that may be active in cancer development. Lots of companies and laboratories have been betting on this."
Dicer enzymes are found in all cells of higher animals, suggesting that it has an ancient evolutionary heritage. Because of its ability to recognize double-stranded RNA, scientists think Dicer's original function may have been to defend cells from certain kinds of viruses.
Having an image of Dicer from Giardia intestinalis, Doudna noted, will help scientists better understand its role across biology."From an evolutionary standpoint, it is very interesting," said Doudna. "What is this enzyme used for in Giardia? We don't know. The Giardia Dicer is smaller than the Dicer found in other eukaryotes and we don't know why that is. What do the bells and whistles on the human enzyme do?"
Knowing Dicer's structure, scientists can now begin to tease out the mysteries of how Dicer functions, Doudna said. In particular, scientists would like to know how Dicer is involved in downstream events, how it hands off the cleaved RNA and directs it to the right gene targets.
Resolving the structure of Dicer, Doudna noted, was a technical challenge as the crystals are small. But she said that the work was facilitated by access to the HHMI-supported crystallography beam lines at the Lawrence Berkeley National Laboratory's Advanced Light Source. The synchrotron at the Advanced Light Source is capable of generating beams of x-rays to very specific wavelengths, which was critical in determining the structure of Dicer.
Additional authors of the new Scie
Source:University of Pittsburgh Medical Center