October 14, 2002

Ancient Defense Mechanism May Still Be Protecting Us

A complex DNA error-correction system that likely evolved from an ancient self-defense mechanism is still active in nearly every organism, turning primeval genetic invaders' tricks against them and into useful cell functions. The mechanism, discovered by researchers at the University of Rochester, ensures that any foreign genetic material that has been inserted into the cell's DNA is neutralized before being passed on to the next generation. The research is published in the September 20 issue of Cell, and is reviewed in the recent issues of Science and Journal of Cell Biology.

"This is exciting research that provides new understanding of how cells control the activity of their genes," says Joseph G. Gall, a cell biologist at the Carnegie Institution in Baltimore. "This work shows once again that basic research on a seemingly obscure topic-how a minute pond organism reproduces-can throw light on important medical issues such as viral infection."

Martin Gorovsky, Rush Rhees Professor of Biology at the University of Rochester, and his post doctoral colleague Kazufumi Mochizuki discovered the mechanism while looking at a single-celled organism called Tetrahymena, which contains two nuclei, the area of a cell where DNA is usually stored. The members of the University team wanted to learn how the cell transfers its genetic code from one of its nuclei to one in its offspring, so they monitored each step as the cell inspected its DNA and passed it to the next generation. That system of checks, which likely also exists in organisms more complex than the protozoan, revealed clues as to how the cell recognizes these harmful invaders by co-opting some of the invader's attributes to help regulate itself.

Gorovsky and Mochizuki showed that short strands of RNA (ribonucleic acid) likely migrate from one nucleus in the parental cell to the other before moving into a third developing nucleus in the progeny cells, all the while comparing one genetic template to the next until a "safe to use" set of genes remain to be given to the cell's offspring.

Nearly all cells house their DNA inside a nucleus, but Tetrahymena houses different versions of its DNA in each of its two nuclei. The smaller nucleus (called the micronucleus) does nothing more than keep the cell's full genome safe, acting as a sort of "lock box." The larger nucleus (called the macronucleus), on the other hand, uses the DNA to regulate the cell's life functions. This macronucleus houses about 15 percent fewer DNA sequences than the smaller one, and when the cell mates to create a new generation of cells, this large macronucleus withers and dies. Before it completely expires, however, the small nucleus steps in and produces a new large and small nucleus set. To make sure no new viral sequences have sneaked into the lock box, the cell checks the DNA of the small, lock box nucleus against the DNA of the old large nucleus and eliminates any foreign material before allowing the new large nucleus to develop.

Gorovsky's team believes that in evolutionarily ancient times, cells had to fight against a variety of assaults just as they must today: viruses attacked cells, injecting their DNA, disrupting normal cell functions; and transposons, bits of nomadic genetic material, would fit themselves in several places in the cell's genome, copying themselves prodigiously and wreaking havoc. To survive, cells evolved a correction system that recognized the invading DNA and either eliminated or silenced it. Gorovsky and Mochizuki propose that the small nucleus "transcribes" into RNA part or all of its DNA, essentially making RNA photocopies of certain DNA sections. These transcriptions include the sections that may have been corrupted by some genetic marauder like a virus or transposon. The transcribed RNAs then migrate out of the small nucleus, through the cell to the large nucleus where they mingle with the macronucleus' DNA. If an RNA comes across a section of DNA that matches the RNA's copy, the RNA self-destructs. This means the only RNAs remaining are copies that match some foreign DNA that sneaked into the lock box of the small nucleus since it last produced the larger one.

These RNAs then head back out of the dying large nucleus toward the new large nucleus of the next generation. There, they look for the matching DNA in the new macronucleus, but this time, instead of self-destructing, they tag the matching, invading DNA sections for destruction.

The result of this complex exchange and re-exchange of RNA strands is that the developing macronucleus now contains only the organism's DNA that was present in both the original macronucleus and the micronucleus, but not any new DNA that could have disastrous effects. The original macronucleus then withers away, leaving the new macronucleus and the micronucleus, both of which divide as the cell divides into identical daughter cells, each with a new set of nuclei.

Gorovsky and Mochizuki are already planning to look deeper into the way the cell's defense mechanism works. One of the main goals will be to identify the function of every protein associated with the RNAs as they go about their job of double checking the cell's genome.

The research done at Rochester was funded by the National Institutes of Health.