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DNA and RNA Revealed: New Roles And New Rules

For many years, when scientists thought about heredity, DNA was the first thing

to come to mind. It’s true that DNA is the basic ingredient of our genes and, as such, it often steals the limelight from RNA, the other form of genetic material inside our cells.

But, while they are both types of genetic material, RNA and DNA are rather different.

The chemical units of RNA are like those of DNA, except that RNA has the nucleotide uracil
(U) instead of thymine (T). Unlike double­ stranded DNA, RNA usually comes as only a single strand. And the nucleotides in RNA contain ribose sugar molecules in place of deoxyribose.
RNA is quite flexible—unlike DNA, which is a rigid, spiral­staircase molecule that is very stable. RNA can twist itself into a variety of complicated, three­dimensional shapes. RNA is also unstable in that cells constantly break it down and must con­ tinually make it fresh, while DNA is not broken down often. RNA’s instability lets cells change their patterns of protein synthesis very quickly
in response to what’s going on around them. Many textbooks still portray RNA as a passive
molecule, simply a “middle step” in the cell’s gene­reading activities. But that view is no longer accurate. Each year, researchers unlock new secrets about RNA. These discoveries reveal that it is truly a remarkable molecule and a multi ­ talented actor in heredity.

Today, many scientists believe that RNA evolved on the Earth long before DNA did. Researchers hypothesize — obviously, no one was around to write this down — that RNA was a major participant in the chemical reactions that ultimately spawned the first signs of life on the planet. RNA World At least two basic requirements exist for making a cell: the ability to hook molecules together and break them apart, and the ability to replicate, or copy itself, from existing information. RNA probably helped to form the first cell. The first organic molecules, meaning molecules containing carbon, most likely arose out of random collisions of gases in the Earth’s primitive atmos­ phere, energy from the Sun, and heat from naturally occurring radioactivity. Some scientists think that in this primitive world, RNA was a critical molecule because of its ability to lead a double life: to store information and to conduct chemical reactions. In other words, in this world, RNA served the functions of both DNA and proteins. What does any of this have to do with human health? Plenty, it turns out. Today’s researchers are harnessing some of RNA’s flexibility and power. For example, through a strategy he calls directed evolution, molecular engineer Ronald R. Breaker of Yale University is developing ways to create entirely new forms of RNA and DNA that both work as enzymes. Breaker and others have also uncovered a hidden world of RNAs that play a major role in controlling gene activity, a job once thought to be performed exclusively by proteins. These RNAs, which the scientists named riboswitches, are found in a wide variety of bacteria and other organisms RNA-Molecules This discovery has led Breaker to speculate that new kinds of antibiotic medicines could be developed to target bacterial riboswitches.

Molecular Editor

Scientists are learning of another way to cus­ tomize proteins: by RNA editing. Although DNA sequences spell out instructions for producing RNA and proteins, these instructions aren’t always followed precisely. Editing a gene’s mRNA, even by a single chemical letter, can radically change the resulting protein’s function. Nature likely evolved the RNA editing function as a way to get more proteins out of the same number of mRNA-small-powerful Recently, molecules called microRNAs have been found in organisms as diverse as plants, worms and people. The molecules are truly “micro,” con­ sisting of only a few dozen nucleotides, compared to typical human mRNAs that are a few thousand nucleotides long. What’s particularly interesting about microRNAs is that many of them arise from DNA that used to be considered merely filler material (see page 14). How do these small but important RNA mole­ cules do their work? They start out much bigger but get trimmed by cellular enzymes, including one aptly named Dicer. Like tiny pieces of genes. For example, researchers have found that the mRNAs for certain proteins important for the proper functioning of the nervous system are particularly prone to editing. It may be that RNA editing gives certain brain cells the capacity to react quickly to a changing environment. Which molecules serve as the editor and how does this happen? Brenda Bass of the University of Utah School of Medicine in Salt Lake City studies one particular class of editors called adenosine deaminases. These enzymes “retype” RNA letters at various places within an mRNA transcript. They do their job by searching for characteris­ tic RNA shapes. Telltale twists and bends in folded RNA molecules signal these enzymes to change the RNA sequence, which in turn changes the protein that gets made. Bass’ experiments show that RNA editing occurs in a variety of organisms, including peo­ ple. Another interesting aspect of editing is that certain disease­causing microorganisms, such as some forms of parasites, use RNA editing to gain a survival edge when living in a human host. Understanding the details of this process is an important area of medical research. Worms with a mutated form of the microRNA let­7 (right) have severe growth problems, rupturing as they develop. microRNAs stick to certain mRNA mole­ cules and stop them from passing on their protein­making instructions. First discovered in a roundworm model system (see Living Laboratories, page 49), some microRNAs help determine the organism’s body plan. In their absence, very bad things can happen. For exam­ ple, worms engineered to lack a microRNA called let­7 develop so abnormally that they often rupture and practically break in half as the worm grows. Perhaps it is not surprising that since microRNAs help specify the timing of an organism’s develop­ mental plan, the appearance of the microRNAs themselves is carefully timed inside a developing organism. Biologists, including Amy Pasquinelli of the University of California, San Diego, are cur­ rently figuring out how microRNAs are made and cut to size, as well as how they are produced at the proper time during development. MicroRNA molecules also have been linked to cancer. For example, Gregory Hannon of the Cold Spring Harbor Laboratory on Long Island, New York, found that certain microRNAs are associ­ ated with the severity of the blood cancer B­cell lymphoma in mice. Since the discovery of microRNAs in the first years of the 21st century, scientists have identified hundreds of them that likely exist as part of a large family with similar nucleotide sequences. New roles for these molecules are still being found.

Healthy Interference

RNA controls genes in a way that was only discov­ ered recently: a process called RNA interference, or RNAi. Although scientists identified RNAi less than 10 years ago, they now know that organisms have been using this trick for millions of years. Researchers believe that RNAi arose as a way to reduce the production of a gene’s encoded protein for purposes of fine­tuning growth or self­defense. When viruses infect cells, for example, they com­ mand their host to produce specialized RNAs that allow the virus to survive and make copies of itself. Researchers believe that RNAi eliminates unwanted viral RNA, and some speculate that it may even play a role in human immunity. Oddly enough, scientists discovered RNAi from a failed experiment! Researchers investi­ gating genes involved in plant growth noticed something strange: When they tried to turn petunia flowers purple by adding an extra “purple” gene, the flowers bloomed white instead. This result fascinated researchers, who could not understand how adding genetic material could somehow get rid of an inherited trait. The mystery remained unsolved until, a few years later, two geneticists studying development saw a similar thing happening in lab animals. The researchers, Andrew Z. Fire, then of the Carnegie Institution of Washington in Baltimore and now at Stanford University, and Craig Mello of the University of Massachusetts Medical School in Worcester, were trying to block the expression of genes that affect cell growth and tissue formation in roundworms, using a molecular tool called antisense RNA. Flowers dna To their surprise, Mello and Fire found that their antisense RNA tool wasn’t doing much at all. Rather, they determined, a double­ stranded contaminant produced during the synthesis of the single­stranded antisense RNA interfered with gene expression. Mello and Fire named the process RNAi, and in 2006 were awarded the Nobel Prize in physiology or medicine for their discovery. Further experiments revealed that the double­ stranded RNA gets chopped up inside the cell into much smaller pieces that stick to mRNA and block its action, much like the microRNA pieces of Velcro discussed above (see drawing, page 28). Today, scientists are taking a cue from nature and using RNAi to explore biology. They have learned, for example, that the process is not limited to worms and plants, but operates in humans too. Medical researchers are currently testing new types of RNAi­based drugs for treating condi­ tions such as macular degeneration, the leading cause of blindness, and various infections, includ­ ing those caused by HIV and the herpes virus.

Dynamic DNA

A good part of who we are is “written in our genes,” inherited from Mom and Dad. Many traits, like red or brown hair, body shape and even some personality quirks, are passed on from parent to offspring. But genes are not the whole story. Where we live, how much we exercise, what we eat: These and many other environmental factors can all affect how our genes get expressed. You know that changes in DNA and RNA can produce changes in proteins. But additional con­ trol happens at the level of DNA, even though these changes do not alter DNA directly. Inherited factors that do not change the DNA sequence of nucleotides are called epigenetic changes, and they too help make each of us unique. Epigenetic means, literally, “upon” or “over” genetics. It describes a type of chemical reaction that can alter the physical properties of DNA without changing its sequence. These changes make genes either more or less likely to be expressed (see drawing, page 31). Currently, scientists are following an intrigu­ ing course of discovery to identify epigenetic factors that, along with diet and other environ­ mental influences, affect who we are and what type of illnesses we might get.

Secret Code

DNA is spooled up compactly inside cells in an arrangement called chromatin. This packaging is critical for DNA to do its work. Chromatin consists of long strings of DNA spooled around a compact assembly of proteins called histones. One of the key functions of chromatin is to control access to genes, since not all genes are turned on at the same time. Improper expression of growth ­promoting genes, for example, can lead to cancer, birth defects or other health concerns. The epigenetic code controls gene activity with chemical tags that mark DNA (purple diamonds) and the tails of histone proteins (purple triangles). These markings help determine whether genes will be transcribed by RNA polymerase. Genes hidden from access to RNA polymerase are not expressed. Many years after the structure of DNA was determined, researchers used a powerful device known as an electron microscope to take pictures of chromatin fibers. Upon viewing chromatin up close, the researchers described it as “beads on a string,” an image still used today. The beads were the histone balls, and the string was DNA wrapped around the histones and connecting one bead to the next. Decades of study eventually revealed that histones have special chemical tags that act like switches to control access to the DNA. Flipping these switches, called epigenetic markings, unwinds the spooled DNA so the genes can be transcribed. The observation that a cell’s gene­reading machinery tracks epigenetic markings led C. David Allis, who was then at the University of Virginia Health Sciences Center in Charlottesville and now works at the Rockefeller University in New York City, to coin a new phrase, the “histone code.” He and others believe that the histone code plays a major role in determining which proteins get made in a cell. Flaws in the histone code have been associated with several types of cancer, and researchers are actively pursuing the develop­ ment of medicines to correct such errors.
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