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Archive for the ‘Interesting Studies’ Category

Unique Change in Protein Structure Guides Production of RNA from DNA

 :: Posted by American Biotechnologist on 11-08-2013

One of biology’s most fundamental processes is something called transcription. It is just one step of many required to build proteins—and without it life would not exist. However, many aspects of transcription remain shrouded in mystery. But now, scientists at the Gladstone Institutes are shedding light on key aspects of transcription, and in so doing are coming even closer to understanding the importance of this process in the growth and development of cells—as well as what happens when this process goes awry.

In the latest issue of Molecular Cell, researchers in the laboratory of Gladstone Investigator Melanie Ott, MD, PhD, describe the intriguing behavior of a protein called RNA polymerase II (RNAPII). The RNAPII protein is an enzyme, a catalyst that guides the transcription process by copying DNA into RNA, which forms a disposable blueprint for making proteins. Scientists have long known that RNAPII appears to stall or “pause” at specific genes early in transcription. But they were not sure as why.

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An Eye in the Sky Makes It Dangerous to Fly

 :: Posted by American Biotechnologist on 10-24-2013

Just 13 days in space may be enough to cause profound changes in eye structure and gene expression, report researchers from Houston Methodist, NASA Johnson Space Center, and two other institutions in the October 2013 issue of Gravitational and Space Research.

The study, which looked at how low gravity and radiation and oxidative damage impacts mice, is the first to examine eye-related gene expression and cell behavior after spaceflight.

“We found many changes in the expression of genes that help cells cope with oxidative stress in the retina, possibly caused by radiation exposure,” said Houston Methodist pathologist Patricia Chévez-Barrios, M.D., the study’s principal investigator. “These changes were partially reversible upon return to Earth. We also saw optic nerve changes consistent with mechanical injury, but these changes did not resolve. And we saw changes in the expression of DNA damage repair genes and in apoptotic pathways, which help the body destroy cells that are irreparably damaged.”

Since 2001, studies have shown astronauts are at increased risk of developing eye problems, like premature age-related macular degeneration. Experts suspect the cause is low gravity, heightened exposure to solar radiation, or a combination of the two.

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Complex Diseases Traced to Gene Copy Numbers

 :: Posted by American Biotechnologist on 10-17-2013

Duke researchers have connected very rare and precise duplications and deletions in the human genome to their complex disease consequences by duplicating them in zebrafish.

The findings are based on detailed studies of five people missing a small fragment of their genome and suffering from a mysterious syndrome of craniofacial features, visual anomalies and developmental delays.

When those patient observations were coupled to analyses of the anatomical defects in genetically altered zebrafish embryos, the researchers were able to identify the contribution specific genes made to the pathology, demonstrating a powerful tool that can now be applied to unraveling many other complex and rare human genetic conditions.

The findings are broadly important for human genetic disorders because copy-number variants (CNVs) — fragments of the genome that are either missing or existing in extra copies — are quite common in the genome. But their precise contribution to diseases has been difficult to determine because CNVs can affect the function of many genes simultaneously.

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A new way to edit RNA

 :: Posted by American Biotechnologist on 10-03-2013

A tiny but unexpected change to a segment of RNA in a single-cell organism looks a lot like a mistake, but is instead a change to the genetic information that is essential to the organism’s survival.

Scientists have discovered this RNA “edit” in Trypanosoma brucei, a parasite that causes sleeping sickness in Africa and Chagas disease in Latin America. Though the organism is a model system for this work, the finding could lead to a new drug target to fight the parasite if higher species don’t share this genetic behavior.

Some of the organism’s genetic activity was already known. In the case of gene products called tRNAs, which help assemble the amino acids that make proteins, T. brucei was known to have only one tRNA with a specific segment of RNA that ensures the tRNA’s proper function. Additionally, examples of RNA editing have been discovered before.

But in this case, the way genetic information necessary for the protein production process was changed – through a swap of three nucleotides for three others that are completely out of place – has never been seen before.

“These are changes for which no chemistry is known and has never been described. We don’t know what enzyme is involved and that is the million-dollar question: What mechanism is doing this? We haven’t a clue,” said Juan Alfonzo, professor of microbiology at The Ohio State University and senior author of the study.

“If the activity is unique to a trypanosome, then you have a good drug target. If it is widespread, then you have to reconsider one more time what coding sequences really mean in the sense that you can indeed change them in a very programmed fashion by activities that don’t exist – that have not been described,” said Alfonzo, also an investigator in Ohio State’s Center for RNA Biology.

The work is the result of Alfonzo’s longtime collaboration with co-lead author Christopher Trotta, senior director of biology at PTC Therapeutics in South Plainfield, N.J.

The study appears online in the journal Molecular Cell and is scheduled for print publication on Oct. 24.

The finding was not only unexpected, but serendipitous. Alfonzo’s lab was analyzing an enzyme affecting T. brucei’s tRNA behavior in response to a request from Trotta, a drug developer who is considered a pioneer of research on tRNAs. To begin the analysis, Alfonzo sought to identify the intron, a specific segment of RNA, that needs to be removed before the tRNA can participate in the selection of the right amino acids during protein production.

This critical function of removing the intron is called splicing – in essence, a pre-requisite chemical reaction affirming that tRNA can deliver the correct instructions for protein production. If a tRNA is not spliced, it will not work in protein production and the cell will die.

The trouble was, Alfonzo couldn’t locate the intron that he knew was there. After multiple attempts, he found that the intron’s sequence in this organism changed after transcription, the point at which a copy of RNA is made from a DNA sequence as the first step of gene expression.

This edit – hard to find because of its odd nature – consisted of a change to three nucleotides, the molecules that form DNA and RNA. Because of its rarity and unusual nature, it is called a noncanonical edit.

“It’s noncanonical because it is not typical. It is completely not typical,” Alfonzo said. “And for the first time, we show the biological significance. We show that if you don’t edit, you don’t splice. This editing is required for splicing, and splicing is required for functionality. Otherwise, cells die.”

Previously known methods of RNA editing include deamination, the removal of sections of molecules from the RNA that change the message from the DNA, and nucleotide insertion, deletion or exchange. The editing described here is a swap of three nucleotides for three others that, according to the rules of biology, do not belong where they end up. This is why it looks like a mistake.

Colleagues have suggested that this edit should have been identified by researchers who do deep sequencing, which involves repeated readings of all nucleotides within an RNA molecule, Alfonzo noted. But he is not surprised that technology didn’t yield these results.

“In massive sequencing, you match RNAs to the sequence in the genome. Any mismatch is called a sequence mistake and is thrown in the trash. So this noncanonical editing may well be in the trash bin of many of these deep sequencing researchers,” he said.

Thanks to Ohio State University for this story.

Regulating Cellular Trafficking

 :: Posted by American Biotechnologist on 09-23-2013

Molecular microbiologists at the University of Southern California (USC) have uncovered intricate regulatory mechanisms within the cell that could lead to novel therapeutics for the treatment of cancer and other diseases. Their findings, which have long-standing significance in the basic understanding of cell biology, appear in the journal Nature Cell Biology.

“Our research reveals a new regulatory mechanism that coordinates two distinct intracellular processes that are critical to cellular homeostasis and disease development,” said Chengyu Liang, M.D., Ph.D., a member of the USC Norris Comprehensive Cancer Center and principal investigator of the study.

The endoplasmic reticulum (ER) and Golgi apparatus are cellular organelles in eurkaryotic organisms where proteins are synthesized and packaged for secretion through the body. The trafficking of proteins between the ER and Golgi must be tightly modulated to maintain the health of the cell and prevent diseases like cancer from taking hold.

“Interest in the role of ER-Golgi network during cancer cell death has been gaining momentum,” said Shanshan He, Ph.D., research associate at the Keck School of Medicine of USC and one of the study’s first authors. “In this study, we identified a novel regulatory factor for the Golgi-ER retrograde transport and a new mechanistic connection between the physiological trafficking and the autophagic transportation of cellular material.”

The researchers discovered that the UV irradiation resistance-associated gene protein (UVRAG), which has been implicated in the suppression of colon and breast cancer, coordinates trafficking of proteins between the ER and Golgi apparatus and also autophagy, the natural process of breaking down cellular components.

“Given that the ER-Golgi network is often dismantled in malignant conditions and that UVRAG is intensively involved in different types of human cancers, this study gives us a new avenue to investigate anti-cancer agents that target UVRAG and/or the ER-Golgi pathway in cancer and other relevant diseases,” Liang said.

Source: University of Southern California – Health Sciences. “Protein identified that regulates cellular trafficking, potential for anti-cancer therapy.” ScienceDaily, 22 Sep. 2013. Web. 24 Sep. 2013.