Scientists create novel RNA repair technology

The new study, published January 17, 2012 in an advance, online edition of the journal ACS Chemical Biology, describes a method to find compounds that target defective RNAs, specifically RNA that carries a structural motif known as an "expanded triplet repeat." The triplet repeat, a series of three nucleotides repeated many more times than normal in the genetic code of affected individuals, has been associated with a variety of neurological and neuromuscular disorders.

"For a long time it was thought that only the protein translated from this type of RNA was toxic," said Matthew Disney, an associate professor at Scripps Florida who led the new study. "But it has been shown recently that both the protein and the RNA are toxic. Our discovery of a small molecule that binds to RNA and shuts off its toxicity not only further demonstrates that the RNA is toxic but also opens up new avenues for therapeutic development because we have clearly demonstrated that small molecules can reverse this type of defect."

In the new research, the scientists used a query molecule called 4', 6-diamidino-2-phenylindole (DAPI) as a chemical and structural template to find similar but more active compounds to inhibit a toxic CAG triplet repeat. One of these compounds was then found effective in inhibiting the RNS toxicity of the repeat in patient-derived cells, which demonstrated an improvement in early-stage abnormalities.

"The toxic RNA defect actually sucks up other proteins that play critical roles in RNA processing, and that is what contributes to these various diseases," Disney said. "Our new compound targets the toxic RNA and inhibits protein binding, shutting off the toxicity. Since the development of drugs that target RNA is extremely challenging, these studies can open up new avenues to exploit RNA drug targets that cause a host of other RNA-mediated diseases."

Disney and his colleagues are already hard at work to extend the lab's findings.

More information: "Chemical Correction of Pre-mRNA Splicing Defects Associated with Sequestration of Muscleblind-Like 1 Protein by Expanded r(CAG)-containing Transcripts," Amit Kumar et al. http://pubs.acs.or … 21/cb200413a

Provided by The Scripps Research Institute (news : web)

New nanotech technique for lower-cost materials repair

In the super-small world of nanostructures, a team of polymer scientists and engineers at the University of Massachusetts Amherst have discovered how to make nano-scale repairs to a damaged surface equivalent to spot-filling a scratched car fender rather than re-surfacing the entire part. The work builds on a theoretical prediction by chemical engineer and co-author Anna Balazs at the University of Pittsburgh.

Their discovery is reported this week in the current issue of Nature Nanotechnology. The new technique has many practical implications, especially that repairing a damaged surface with this method would require significantly smaller amounts of material, avoiding the need to coat entire surfaces when only a tiny fraction is cracked, says team leader and UMass Amherst polymer scientist Todd Emrick.

"This is particularly important because even small fractures can then lead to structural failure but our technique provides a strong and effective repair. The need for rapid, efficient coating and repair mechanisms is pervasive today in everything from airplane wings to microelectronic materials to biological implant devices," he adds.

At nano-scale, damaged areas typically possess characteristics quite distinct from their undamaged surrounding surface, including different topography, wetting characteristics, roughness and even chemical functionality, Emrick explains. He adds, "Anna Balazs predicted, using computer simulation, that if nanoparticles were held in a certain type of microcapsule, they would probe a surface and release nanoparticles into certain specific regions of that surface," effectively allowing a spot-repair.

This vision of capsules probing and releasing their contents in a smart, triggered fashion, known as "repair-and-go," is characteristic of biological process, such as in white blood cells, Emrick adds.

He says the experimental work to support the concept required insight into the chemistry, physics and mechanical aspects of materials encapsulation and controlled release, and was achieved by collaboration among three polymer materials laboratories at UMass Amherst, led by Alfred Crosby, Thomas Russell and himself.

The researchers show how using a polymer surfactant stabilizes oil droplets in water (in emulsion droplets or capsules), encapsulating nanoparticles efficiently, but in a manner where they can be released when desired, since the capsule wall is very thin.

"We then found that the nanoparticle-containing capsules roll or glide over damaged substrates, and very selectively deposit their nanoparticle contents into the damaged (cracked) regions. Because the nanoparticles we use are fluorescent, their localization in the cracked regions is clearly evident, as is the selectivity of their localization."

Using rapid and selective deposition of sensor material in damaged regions, their innovative work also provides a precise method for detecting damaged substrates, he stresses. Finally, the new encapsulation techniques allow delivery of hydrophobic objects in a water-based system, further precluding the need for organic solvents in industrial processes that are dis-advantageous from an environmental standpoint.

Emrick says, "Having realized the concept experimentally, looking forward we now hope to demonstrate recovery of mechanical properties of coated objects by adjusting the composition of the nanoparticles being delivered."

The work was supported by the National Science Foundations' (NSF) Materials Research Science and Engineering Center on Polymers at UMass Amherst, an NSF Integrative Graduate Education and Research Traineeship (IGERT) award, the NSF Center for Hierarchical Manufacturing, the U.S. Department of Energy and its Office of Basic Energy Science.

Story Source:

The above story is reprinted from materials provided by University of Massachusetts Amherst.

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Journal Reference:

Katrina Kratz, Amrit Narasimhan, Ravisubhash Tangirala, SungCheal Moon, Ravindra Revanur, Santanu Kundu, Hyun Suk Kim, Alfred J. Crosby, Thomas P. Russell, Todd Emrick, German Kolmakov, Anna C. Balazs. Probing and repairing damaged surfaces with nanoparticle-containing microcapsules. Nature Nanotechnology, 2012; DOI: 10.1038/nnano.2011.235

Note: If no author is given, the source is cited instead.

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Biochemists identify new genetic code repair tool

Clemson University researchers recently reported finding a new class of DNA repair-makers.

Clemson biochemist Weiguo Cao studies how cells repair damaged DNA. The finding from Cao's lab in the Clemson Biosystems Research Complex in collaboration with computational chemist Brian Dominy appeared in the Sept. 9 issue of The Journal of Biological Chemistry: "A new family of deamination repair enzymes in the uracil DNA glycosylase superfamily by Hyun-Wook Lee, Brian N. Dominy and Weiguo Cao."

"DNA is a string of a long molecule composed of four building blocks: A for adenine, T for thymine, G for guanine and C for cytosine. The heredity of all organisms is determined by the pairing of A with T and G with C," said Cao, a professor in the genetics and biochemistry department.

DNA is constantly assaulted by various stresses. A common type of damage is modification of three out of the four building blocks for genetic code, A, G, C by a chemical process called deamination. The genetic consequence of deamination is that it will change the pairing of the genetic code. For example, the deamination of C (cytosine) will generate U (uracil). Instead of pairing with G as C will do, U pairs with A. In so doing, it changes the genetic program inside the cell and may cause dangerous mutations resulting in disease.

To ensure the integrity of the genetic material, cells are equipped with a "molecular toolkit" for repairing DNA damage. The toolkit is comprised of a variety of different molecules — called enzymes — that have evolved to repair different types of DNA damage. One of the DNA repair enzymes the Cao lab studies is called uracil DNA glycosylase (UDG). As it's name indicates, it is traditionally known as an enzyme that removes uracil from DNA. Because deamination of C (cytosine) is a very common type of damage found in DNA, UDG has been found in many organisms and researchers have grouped them into five families in the so-called UDG superfamily.

In their most recent work, Cao and his colleagues discovered a new class of enzymes in that superfamily that lack the ability to repair uracil. A further study showed that this class of enzymes, instead, is engaged in the repair of deamination on the different building block adenine. This caught them by surprise because all known UDG enzymes are capable of uracil repair.

To further understand how this new class of enzymes works as a tool for repair, Cao and Dominy combined computational and biochemical methods to pinpoint the critical part of the repair machine that is responsible.

"What we learned from this work is that DNA repair toolkits have an amazing ability to evolve different repair functions for different kinds of DNA damage," Cao said. "This work also demonstrates how a combination of research approaches from different disciplines makes the discovery possible."

"Collaborative efforts involving computational and experimental investigative methods can greatly enhance the efficiency of scientific discovery, as well as provide more thorough answers to very important scientific questions," Dominy said. "In my opinion, the collaborative efforts between our two groups have demonstrated the substantial value of such interactions."

Provided by Clemson University (news : web)