Discovery Of New Mode Of Gene Regulation In Mammals

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Discovery Of New Mode Of Gene Regulation In Mammals

http://www.medicalnewstoday.com/articles/114581.php

Researchers at the University of California, Santa Cruz, have

discovered a type of gene regulation never before observed in mammals-

-a " ribozyme " that controls the activity of an important family of

genes in several different species.

The findings, published in the journal Nature, describe a new and

surprising role for the so-called hammerhead ribozyme, an unusual

molecule previously associated with obscure virus-like plant

pathogens called viroids. The UCSC researchers found the ribozyme

embedded within certain genes in mice, rats, horses, platypuses, and

several other mammals. The genes are involved in the immune response

and bone metabolism.

" The unique thing about these ribozymes is that they control the

expression of the genes they're embedded in, " said Monika Martick, a

UCSC postdoctoral researcher and first author of the Nature paper.

A ribozyme, or " RNA enzyme, " is an RNA molecule that can catalyze a

chemical reaction. RNA is better known for its ability to encode

genetic information, while most biological reactions are carried out

by enzymes made of protein. Scientists are discovering, however, that

RNA is a remarkably versatile type of molecule.

" RNA can function in the biology of organisms in more ways than we

tend to give it credit for, " said coauthor Lucas Horan, a graduate

student in molecular, cell, and developmental biology at UCSC.

When a gene is activated or " expressed, " its DNA sequence on the

chromosome is transcribed into an RNA molecule called a messenger

RNA. The messenger RNA sequence is then translated into the amino

acid sequence of a protein molecule, and the protein then carries out

the gene's function in the cell.

In the genes studied by Martick and Horan, the messenger RNA contains

sequences that assemble to form an active hammerhead ribozyme. The

hammerhead ribozyme is a self-cleaving molecule that essentially cuts

itself in two. This self-cleaving action in the messenger RNAs

effectively turns off the genes by preventing protein translation.

Presumably, another mechanism exists to turn on the genes by stopping

the self-cleaving action of the ribozyme.

" We don't know what the switch is to shut off the action of the

ribozyme, but we assume there is one, " Martick said.

She and her coauthors are all affiliated with UCSC's Center for the

Molecular Biology of RNA, directed by Harry Noller, Sinsheimer

professor of molecular biology. As a graduate student working with

, professor of chemistry and biochemistry, Martick had

determined the three-dimensional structure of the hammerhead ribozyme

(see earlier press release at http://press.ucsc.edu/text.asp?

pid=907).

and his research group have been working on the structure and

mechanism of the hammerhead ribozyme since before his arrival at UCSC

in 1998. " This is the most remarkable and unexpected discovery I have

seen during that time, " he said.

For the new study, Martick teamed up with Horan, a graduate student

in Noller's lab. and Noller are both coauthors of the Nature

paper.

" Monika clued me in that she had found something interesting, and we

decided to try to figure out what was going on, " Horan said. " She had

just finished her Ph.D., and I was working on something else, but we

got some preliminary data and it turned out to be a very fruitful

collaboration; it's the kind of interaction that the RNA Center is

meant to stimulate. "

Martick performed the initial searches that turned up the hammerhead

ribozyme sequences in the mouse and rat genomes. Then she and Horan

did more exhaustive searches of the genomic sequences of other

organisms, using the UCSC Genome Browser and other databases. They

found the ribozyme in related genes in the mouse, rat, horse, and

platypus, and in unknown genes in five other mammals.

" We used to think the hammerhead ribozyme was restricted to obscure

plant viruses, but it now looks like it is featured much more

prominently in mammalian biological systems, " said.

Laboratory experiments showed that the messenger RNAs containing the

embedded sequences form an active ribozyme and that the ribozyme

decreases gene activity in mammalian cells.

" This mode of gene regulation hadn't been seen before in mammals, "

Horan said. " Because it occurs in such a wide variety of organisms,

including the platypus, it must have been around since the early

mammalian ancestors. "

The researchers did not find the ribozyme sequence in the

corresponding human genes, however, suggesting that a different

mechanism regulates those genes in humans.

" These genes are involved in the immune response and in bone

metabolism, so they are being intensively studied on two fronts, "

Martick said. " It's important to understand how that system is

regulated and if the rodent system is regulated differently from the

human system. "