There are always exceptions to a rule, even one that has prevailed for more than three decades, as demonstrated by a Cold Spring Harbor Laboratory (CSHL) study on RNA splicing, a cellular editing process. The rule-flaunting exception uncovered by the study concerns the way in which a newly produced RNA molecule is cut and pasted at precise locations called splice sites before being translated into protein.
"The discovery of this exception could impact current ideas on how missteps in splicing triggered by mutations in the DNA sequence can lead to diseases such as cancer and various genetic disorders," says CSHL Professor Adrian Krainer, Ph.D., who led the research. The study appears in the May 15 issue of Genes & Development.
For a protein to be synthesized by the cell, the instructions encoded within that protein's gene have to be first copied from DNA into RNA. This initial copy, called a pre-messenger RNA, is then edited much like film footage, where the unnecessary bits—strings of nucleotides called introns—are snipped out and the remaining bits (called exons) are spliced together. For the cut-and-paste mechanism to work correctly, the cell's splicing machinery initially has to be guided to the correct splice site at the beginning of each intron on the target pre-mRNA by another, smaller RNA called U1.
U1 finds the right spots, or splice sites, by lining up against the target RNA and pairing its own RNA nucleotides or bases (the "letters" of the RNA code, A, U, C, G) with those of the target RNA such that its A nucleotide pairs with the target's U, and its C nucleotide pairs with the target's G nucleotide, or vice-versa. U1's ability to recognize splice sites at the beginning of introns is the strongest when up to 11 bases are paired up with their partners on the target RNA, but in most cases, fewer base pairs are formed
Two years ago, Krainer and postdoctoral researcher Xavier Roca discovered, however, that the U1 RNA could recognize even seemingly imperfect splice sites that did not appear to have the correct matching RNA sequence. Instead of lining up against the first RNA base of the target intron's RNA sequence, U1 can sometimes slide down the sequence to the next base if this shift will allow more of the U1 bases to pair up with the target's bases and thereby produce a stronger match.
Krainer and Roca have now found a second, and much more prevalent, alternative option. Instead of shifting away from the first base, they show using a combination of experimental and computational approaches that one or more bases on either U1 or its target can "bulge out"—or pull away from the lineup—if this allows the surrounding nucleotides to produce a stronger match between U1 and the target.
Based on studying splice sites in about 6,500 human genes, they estimate that up to 5% of all splice sites, present in 40% of human genes use this "bulge" mechanism to be recognized. Interestingly, some of these atypically recognized sites occur within genes which when mutated lead to disease, and others are sites where alternative splicing—allowing a single pre-mRNA to give rise to different proteins—can occur.
"This study expands what we thought were the rules for splice site recognition by U1," said Michael Bender, Ph.D., who oversees RNA processing grants at the National Institutes of Health's National Institute of General Medical Sciences (NIGMS), which partially supported the study. "By extending our understanding of how the splicing process works, the findings may help us pinpoint the splicing defects that underlie certain diseases and develop new therapeutics to treat them."
The work was supported by a National Institutes of Health grant (GM42699).
"Widespread recognition of 5' splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides" appears in the May 15th issue of Genes & Development. The full citation is: Xavier Roca, Martin Akerman, Hans Gaus, Andrés Berdeja, C. Frank Bennett and Adrian R. Krainer. The paper can be downloaded at http://genesdev.cshlp.org/content/26/10/1098.full
About Cold Spring Harbor Laboratory
Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 360 scientists strong and its Meetings & Courses program hosts more than 12,500 scientists from around the world each year to its Long Island campus and its China center. Tens of thousands more benefit from the research, reviews, and ideas published in journals and books distributed internationally by CSHL Press. The Laboratory's education arm also includes a graduate school and programs for undergraduates as well as middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island.
Hema Bashyam | EurekAlert!
Bacteria as pacemaker for the intestine
22.11.2017 | Christian-Albrechts-Universität zu Kiel
Researchers identify how bacterium survives in oxygen-poor environments
22.11.2017 | Columbia University
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Business and Finance
22.11.2017 | Physics and Astronomy
22.11.2017 | Physics and Astronomy