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Paradox of genome protection

Yao lab discovers how curious pond microbe Tetrahymena routinely eliminates parts of its own DNA to safeguard its genetic blueprint
Dr. Meng-Chao Yao holding DNA and RNA injection needle
Dr. Meng-Chao Yao displays a needle used for injecting DNA and RNA into Tetrahymena, while research technicians Xiaohui Xi (left) and Patrick Fuller (center) look on. Yao discovered that the pond microbe uses a novel DNA elimination strategy to protect its genome. Photo by Todd McNaught

Students of biology learn that DNA is life's sacred molecule, a vault of information in the cell's nucleus that must be protected from mutation. If its integrity is compromised, the outcome can include abnormal development, disease and defects passed on to successive generations.

Apparently, that bit of wisdom has escaped Tetrahymena thermophila, a lowly single-celled pond microbe that actually eliminates parts of its genetic blueprint as a routine part of its existence. Just why and how it does so has puzzled scientists-until now.

New research from the laboratory of Dr. Meng-Chao Yao in the Basic Sciences Division suggests this seemingly self-destructive-and extraordinarily complex-behavior most likely evolved as a strategy to protect the genome from corruption.

The discovery may benefit biologists as much as it does Tetrahymena: Yao speculates that with a few modifications, the organism's system for deleting parts of its own DNA might someday afford geneticists an effective new strategy to "knock out" genes in laboratory animals. Targeted elimination of genes allows scientists to understand a gene's contribution to normal development or to diseases such as cancer.

The study, as well as an accompanying review, appears in the June 6 issue of Science. Co-authors include Patrick Fuller and Xiaohui Xi, research technicians in the Yao lab who performed most of the experiments. The National Institute of General Medical Sciences, which has supported Yao's work for the last 25 years, funded the research.

Yao, who began studies of Tetrahymena's genetic acrobatics while a graduate student in the 1970s, referred to the discovery as "a light in a 30-year tunnel."

"The phenomenon of DNA rearrangement in Tetrahymena and related organisms has kept us busy for a long time," he said. "It's such a well-regulated process in the cell, but we don't know how and why it evolved. It's a topic that has fascinated scientists because it changes DNA, which we know is the most important molecule for preserving information.

"This study begins to answer questions regarding the mechanism, evolution and biological role of the process, and that's what I'm most excited about."

Tetrahymena's genetic mystique arises from a curious feature of all ciliates, the family of single-celled creatures named for the hair-like structures, known as cilia, which line their surfaces. While most cells have a single nucleus, the "organ" that houses the chromosomes, ciliates have two-known as a micronucleus and a macronucleus (called mic and mac, for short). The mic serves as the genetic vault that is faithfully preserved from one generation to the next. The mac, which programs the cell's day-to-day operations, starts out as an exact replica of the mic but undergoes wild DNA rearrangements after the cell reproduces. Each time a cell reproduces, the old mac is destroyed and new one is created from the mic.

Although dramatic,Tetrahymena's DNA reshuffling in the mac isn't random. The process involves the targeted elimination of about 15 percent of the genome that is presumably needed only for reproduction, if anything, and not for other metabolic activities.

What has puzzled scientists is that the deleted chunks of DNA contain no obvious common features, raising questions as to how Tetrahymena can distinguish those sequences that are destined for destruction from those to be preserved with such precision.

To explore this phenomenon further, Yao's group decided to see what would happen if they injected a foreign gene-one from the bacterium E. coli-into Tetrahymena's micronucleus. To their surprise, the gene was deleted from the macronucleus, suggesting that the mic is able to survey its genome for the presence of foreign DNA and to somehow communicate to the mac that the foreign DNA should be removed.

How might the mic issue the command to the mac that foreign or other unwanted DNA segments should be deleted? Yao based his next experiment on previous studies that suggested that RNA might somehow be involved in the process.

RNA has often been called a messenger molecule because its primary role is to communicate the information buried in the DNA code to the machinery of the cell that produces proteins. Although chemically similar, RNA differs from DNA in that it is a single-stranded molecule rather than a double helix. One of the two DNA strands of each gene can serve as a template to make a unique RNA molecule, which is an exact complement to that DNA strand.

Signal for destruction

Over the past few years, scientists have discovered an ever-growing repertoire of activities for RNA other than its role in protein synthesis. One of the most intriguing is a process known as RNA interference, or RNAi, in which RNA molecules "silence" their cognate genes, effectively preventing them from being turned on and directing the production of proteins.

Previous studies had shown that unlike the case for most genes, mic genes destined for elimination in the mac use both strands of their DNA as templates for RNA production. The two RNA strands, which are complementary to one another, can stick together to form a double-stranded RNA molecule. Yao suspected that the production of these double-stranded RNAs might serve as the destruction signal from the mic.

To test this directly, the group injected artificially produced double-stranded RNAs produced from three different genes intoTetrahymena. When they examined the macronucleus, they found those genes were deleted.

Yao said that Tetrahymena's ability to delete sequences may represent an ancient process that first evolved to protect the cell against transposons, mysterious bits of DNA of unknown origin that can multiply and "hop" to new sites in the genome, causing mutation. Transposons, whose behavior has earned them the nickname of "selfish DNA," constitute roughly half the human genome.

"It has always been a question as to how a cell can defend itself against transposons," he said. "Tetrahymena's strategy is a little like adaptive immunity in our own bodies, which allows us to defend ourselves against viruses or bacteria that our immune systems have never seen before."

Laboratory tool

The process is most likely related to the RNA interference strategy used to silence genes in other organisms-expect that it's permanent.

"It's interesting because RNAi is such a widely occurring phenomenon, found in plants and animals," Yao said. "Yet no one has ever seen it used to actually delete DNA. Now that this process has been identified, it will be interesting to see whether it occurs in other organisms."

Because targeted deletion of genes in the laboratory is a critical strategy for uncovering a gene's function, Yao's discovery is likely to be of interest to biologists in many fields. To be adapted as a lab tool, scientists will first need to identify the proteins that receive the message from the RNA and carry out the actual cutting and removal of the DNA.

"First we need to understand the mechanism of how the DNA actually gets deleted," Yao said, whose lab has begun work on this problem. "There is no parallel in other biological systems."

Which clearly puts Tetrahymena at the head of its class.

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