Navigation Links
Advanced genomics and proteomics improve the diagnosis and treatment of a deadly lung disease

A team of Howard Hughes Medical Institute (HHMI) scientists has peeled back some of the mystery of how cells are able to turn off genes selectively to control critical events of development. The new insights arise from the first clear molecular images of the structure of Dicer, an enzyme that enables cells to dissect genetic material precisely.

The finding, which is reported in the January 13, 2005, issue of the journal Science by an HHMI research team at the University of California, Berkeley, provides scientists with new information about a mechanism that enables cells to silence genes, a process that governs key developmental events ranging from brain development to stem cell differentiation.

The study was led by Jennifer A. Doudna, a Howard Hughes Medical Institute investigator at the University of California, Berkeley. Doudna's research team used x-ray crystallography to assemble a detailed three-dimensional picture of an enzyme known as Dicer. In cells, Dicer jumpstarts RNA interference, a process that causes genes to be turned off and which, in turn, prompts a host of key developmental events.

With the structure of Dicer solved, Doudna's group showed that the enzyme is more than a molecular cleaver -- it also carefully measures and snips strands of RNA into precise increments. When Dicer cleaves large strands of RNA into smaller fragments, it initiates the process of RNA interference, which can turn genes off and thereby dictate key developmental events.

"The bottom line we've learned from the structure is that Dicer is a molecular ruler," Doudna explained. "It gives us a lot of insight into how the mechanism works."

Dicer, which is ubiquitous in the cells of higher animals, including humans, is a widely studied molecule. It was first discovered in 2001 by Gregory J. Hannon, an HHMI investigator at Cold Spring Harbor Laboratory, and has become a powerful laboratory tool to study cancer and other developmental events thr ough its ability to harness the RNA interference pathway and selectively switch off genes.

"We knew what the protein did," said Hannon. "We knew it was an enzyme and that it recognized double-stranded RNA and cut it into pieces. But we didn't have any clue how Dicer made the measurement and figured out where to make the cut."

Doudna and her colleagues solved the structure of a Dicer enzyme obtained from the parasite Giardia intestinalis using x-ray crystallography, a technique that enables scientists to construct pictures of biological molecules in superb three-dimensional detail. When crystal samples of molecules like Dicer are exposed to x-rays, the x-ray beams are scattered in a way that helps researchers define the overall structure of the crystallized protein, as was the case with Dicer. Knowing how the atoms of specific molecules are arranged permits researchers to tease out their functional features and show how they go about their business inside a cell. In the case of Dicer, it shows how the enzyme recognizes RNA and snips it into precise increments.

"The fact that it makes these specific sized RNAs is important to the process," Doudna said. The small RNA fragments created by Dicer are then assimilated into large multiprotein complexes and guide those molecules to destinations in the cell where they turn off genes.

"The size of these small RNAs is a determinant of their function," Hannon explained. "If the RNAs are too big or too small, they don't make it into the effector complexes."

Through its role in helping cells to turn off gene expression, Dicer is believed to be instrumental in initiating some of the critical processes of development. For example, scientists speculate that the RNA interference pathway plays a role in prodding blank-slate stem cells down developmental pathways to become specific kinds of cells or tissues. It may also play roles in maintaining cells, rearranging genomes and laying down the arch itecture of the brain, for example.

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 nce paper are Ian J. MacRae, Kaihong Zhou, Fei Li, Adrian Repic, Angela N. Brooksand W. Zacheus Cande of the University of California, Berkeley and Paul D. Adams of the Lawrence Berkeley National Laboratory.


Source:University of Pittsburgh Medical Center

Related biology news :

1. Applied Biosystems Introduces Advanced Gene Expression Service Provider Program
2. Bevacizumab Combined With Chemotherapy Improves Progression-Free Survival for Patients With Advanced Breast Cancer
3. New comparative toxicogenomics database
4. Measuring the impact of post-genomics on Mediterranean populations
5. Owl genomics presents a HEPATOCHIP for diagnosis of non-alcoholic steatohepatitis
6. Enlisting genomics to understand flu evolution
7. Drawing with DNA: Bioart illuminates genomics
8. Study reveals genomics of inflammation from severe injury
9. NIH launches comprehensive effort to explore cancer genomics
10. Environmental metagenomics diagnosing extreme environments, tapping opportunities for clean energy
11. Ticks, flukes, and genomics: Emerging pathogens revealed
Post Your Comments:

(Date:9/30/2015)... Calif. , Sept. 30, 2015  With nearly ... the number of new SCIs estimated to reach 12,500 ... Southern California Resource Services for Independent Living ... ILCs in California opening doors ... range of programs and services, notably assistive technology services ...
(Date:9/29/2015)... Sept. 29, 2015 News facts: ... while also saving energy , Minimized design shrinks ... Power Active Mode and embedded Fujitsu PalmSecure authentication enable ... Fujitsu today shows that good things come in ... models to its enterprise desktop and mobile portfolio. Featuring ...
(Date:9/28/2015)...  The monitoring of vital signs, such as ... an essential component of patient assessment. Changes in ... a patient,s condition. However, in general care areas ... during routine observation rounds only once every four ... these observation rounds, the warning signs can go ...
Breaking Biology News(10 mins):
... popular with consumers who like the convenience and ... table grapes fresh and increase shelf life, scientists ... alternatives to conventional packing methods. Researchers from the ... ARS) have developed and tested an effective new ...
... OHLoblolly pine bark is the primary component of nursery ... shortage of the widely used organic material is prompting ... recent study by James E. Altland and Charles Krause ... Agricultural Research and Development Center was designed to determine ...
... within patient records or detailed in newspaper clippings can ... the discovery of trends that were previously overlooked, according ... interactive maps and graphs, combined with word search interfaces, ... the spread of Swine flu," said Frank Hardisty, research ...
Cached Biology News:
(Date:10/8/2015)... 2015  Sigma-Aldrich Corporation (NASDAQ: SIAL ) ... within its Applied Diagnostics and Testing business segment ... product line with ten certified Snap-N-Spike ® ... and their stable-labeled internal standards. These new solution ... taurocholic acid and native and deuterium-labeled analogs of ...
(Date:10/7/2015)... India , October 8, 2015 /PRNewswire/ ... --> Medical biotechnology accounts for largest ... of bioinformatics in drug discovery and development ... . ... On the basis of applications, the ...
(Date:10/7/2015)... , Oct. 7, 2015  ChromaDex Corp. (OTCQX: ... nutritional ingredients that creates science-based solutions for dietary ... and pharmaceutical products, today announced that the October ... and Founder, is now available for on-demand viewing ... -->   --> ...
(Date:10/7/2015)... RADNOR, Pa. , Oct. 7, 2015   ... global, independent provider of laboratory products, services and ... Technologies Inc. (PTI), a specialty solvent company that ... solvents. This acquisition will enhance VWR,s growing laboratory ... its laboratory and biopharmaceutical manufacturing customers. ...
Breaking Biology Technology:
... JOLLA, Calif., Oct. 20, 2011 Regulus Therapeutics ... development of innovative medicines targeting microRNAs, and collaborators at ... Center today announced the publication of new pre-clinical research ... et al., Nature , October 20, 2011). ...
... cell carcinomas are amongst the most frequent cancers in ... like many other human cancers, contain particular cancer cells, ... potential that sustain tumor growth. Little is known about ... High level of VEGF expression in skin cancer ...
... Researchers at Purdue University and the National Institute of ... enough to fit on a computer chip that converts ... that might have applications in more advanced sensors, communications ... very high rates, corresponding to hundreds of billions of ...
Cached Biology Technology:
Mouse monoclonal [CIa] to Ia Antigen (Biotin) ( Abpromise for all tested applications)....
Anti-Dardarin Immunogen: Synthetic peptide from rat LRRK2. Available Date: 38814...
Mouse monoclonal [15-2] to Mannose Receptor (Biotin) ( Abpromise for all tested applications). entrezGeneID: 4360 SwissProtID: P22897...
Purified Mouse anti-Hu LAT (pY226) Storage Temperature: Refrigerate(2 to 8C)...
Biology Products: