A team led by Craig Pikaard, Ph.D., Washington University in St. Louis professor of biology in Arts & Sciences, has made a breakthrough in understanding the phenomenon of nucleolar dominance, the silencing of an entire parental set of ribosomal RNA genes in a hybrid plant or animal.

Since the machinery involved in nucleolar dominance is some of the same machinery that can go haywire in diseases such as cancer, Pikaard and his collaborators' research may have important implications for applied medical research.

Nucleolar dominance occurs when nucleoli, protein-rich, dense regions of RNA within the nucleus, form on the chromosomes inherited from one parent, but not on the chromosomes inherited from the other parent. Expression of ribosomal RNA genes drives the formation of these nucleoli. The hybrid, a result of a cross-breeding of two different species, always "chooses" to express the ribosomal RNA genes of one particular parental species, regardless of whether that species happens to be the maternal or paternal parent.

Ribosomal RNAs, or rRNAs, are a major component of the ribosomes, the protein manufacturers of the cell. Because rRNA genes are highly redundant, cells use nucleolar dominance to control the dosage of ribosomes in an organism.

As per Pikaard, if scientists could harness the silencing machinery involved in nucleolar dominance to limit the expression of rRNA genes, they could potentially slow the growth rate of tumor cells and thereby slow the progression of diseases like cancer.

In cancer cells, nucleoli are conspicuously large because of a dramatic increase in the transcription of rRNAs, which in turn leads to an increase in the production of ribosomes. This escalation in ribosome activity means that the cell can synthesize proteins at an alarmingly rapid rate, which contributes to the out-of-control cell proliferation that is the disease's trademark.

Completely silencing all ribosomal genes would not be a viable therapeutic approach for cancer patients because ribosomes are necessary for survival. But Pikaard and his collaborators' research suggests that small interfering RNAs (siRNAs) can direct silencing agendas that are much more sophisticated than an all or nothing approach.

"Dr. Pikaard's study demonstrates the potential of a plant model system to yield important molecular details on how cells silence large clusters of genes," said Anthony Carter, Ph.D., who oversees gene regulation grants at the National Institutes of Health's National Institute of General Medical Sciences, which partially supported the research. "His findings on the control of a major class of RNA found in all cells offer new insights into gene silencing mechanisms."

Pikaard and his collaborators' work, which was published in Molecular Cell on Dec. 4, is also one of the first to demonstrate how siRNAs can play a role in controlling the dosage of vital genes. The research was supported by the National Institutes of Health and the National Science Foundation.


Posted by: Emily    Source

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