Gene control: curiosity and the cat box.

Gene control: Curiosity and the cat box

Researchers this week reported new and surprising observations about a family of proteins that control gene activity in human and other cells. Their report provides a glimpse of one of the most fundamental "on-off" switches in the biological machine, and suggests that mechanisms of gene regulaion are even more mysterious and subtle than previously assumed.

Scientists have known for decades that within DNA strands reside coded instructions for a spectrum of biological functions, from DNA replication to the production of enzymes and other proteins. In a simplified view, segments of DNA, called genes, serve as blueprints for the production of particular proteins. But the process is not a one-way street; certain specialized proteins themselves bind to DNA, where they can regulate the activity, or "expression," of genes.

Little is known about these DNA-binding proteins, but one thing is clear: They are critical to any "decision" by a piece of DNA to either replicate itself or initiate transcription -- the first stage in the process that leads to a protein's production. An understanding of this mechanism of gene regulation might someday enable scientists to control or correct a host of genetic errors, from embryo defects due to aberrant protein synthesis to cancer -- the result of uncontrolled DNA replication and cell division.

Robert Tjian of the Howard Hughes Medical Institute at the University of California, Berkeley, and his colleagues worked with a family of DNA-binding proteins that specifically bind to a DNA region featuring the base sequence code GCCAAT. Scientists find the GCCAAT motif (often called the CCAAT-box) in various places along DNA strands in viruses, yeasts, mammals and other organisms, where it has been associated with DNA transcription and replication. The researchers cloned for the first time several individual members of this mixed family of DNA-binding proteins, and found to their surprise that even a single variety of protein could initiate both transcription and replication.

"Before this we had a family of proteins, and we could say members of this family are involved in both transcription and replication. However it was not clear whether ... all of them showed the same activities or whether some would do one thing and others would do another," says Nicolas Mermod of the research team. "Now we know that the same protein can do it all."

In related studies, the researchers appear to have settled a longstanding question by showing that in the family they examined, a single gene can code for a spectrum of CCAAT-box-binding proteins. Molecules of messenger RNA--key "middlemen" in the process of protein synthesis -- apparently can be cut into pieces, "shuffled" and then spliced together in more than one way before being used as templates in the protein production process. This method of creating a variety of proteins, or "family members," from a single gene has never before been associated with genes affecting transcription. It provides a mechanism for a single DNA site to respond to different, related proteins.

The research, which appears in the July 21 NATURE, provides a new generation of questions about gene regulation. What is the significance of the different forms of regulatory proteins? If a single version can perform at least two distinct functions, what factors determine the job it will actually do? And perhaps most intriguing: What regulates the splicing of messenger RNA, and thus regulates the ultimate diversity of these regulatory proteins?

For now, says Nicholas J. Short of King's College, London, the functional differences between the family members "remain obscure," although "it is conceivable that each form could have subtly different effects on transcription or DNA replication, perhaps by interacting in different ways with some of the other protein factors involved in these processes." In an editorial accompanying the research, the adds, "The potential complexity of the system is staggering."