UCSF-led scientists have identified the first "master" molecule in the cell nucleus that controls the action of hundreds of different genes at once through its action on enzymes. The broad-acting molecule affects enzymes that restructure chromosomes, exposing genes to proteins that can then trigger key gene processes, including the start of protein production and copying and repairing of genes.
The molecule's broad effect on a number of genes may allow organisms – including humans -- to respond quickly to stress, the scientists say. The research finding is based on studies of yeast, but the same molecule is present in humans and all higher organisms. Mutations that affect enzymes involved in chromosome restructuring have been linked to human cancers.
The study is published by SCIENCE through its Science Express web site. The paper will appear in a later print issue of SCIENCE.
"Many enzymes have been identified that modify chromosome structure and trigger gene transcription, but this is the first example of a molecule that regulates these restructuring enzymes and can affect many, many genes at once," said Erin O'Shea, PhD, a Howard Hughes Medical Institute Investigator and professor of biochemistry at UCSF. O'Shea is senior author on the paper. (Transcription is the first key gene process that ultimately leads to the synthesis of new proteins.)
"This molecule's action might allow the cell to regulate the activity of a number of genes in response to stress," O'Shea said. "Chromosome-altering enzymes control important genes in cells. Mutations in the corresponding human enzymes predispose people to a variety of cancers."
The SCIENCE paper clarifies how one molecule, known as inositol polyphosphate, regulates two chromosome-modifying enzymes inside yeast cells. In the same issue of SCIENCE, a team led by researchers at the National Institutes of Health reports results from test tube experiments also showing the molecule controls these enzymes, plus a third that similarly modifies chromosome structure. Together, the two papers show that three enzymes, controlling the action of many hundreds of genes, are themselves regulated by this single inositol polyphosphate molecule.
In the nucleus of cells of all higher organisms, from yeast to humans, DNA is bound to proteins called histones and organized to form basic repeating elements of the chromosome, known as nucleosomes. The packaging of DNA into nucleosomes inhibits "unintended" gene transcription by physically limiting the ability of key proteins to access the DNA. In the past few years, scientists have identified several enzyme complexes that alter the nucleosome structure to allow access to DNA, and gene transcription to begin.
A number of these enzymes that are powered by the cell's energy molecule ATP are called "ATP-dependent chromatin remodeling complexes." Although these enzymes have been studied a great deal, little is known about how they are regulated, the scientists write. The new research shows that the small molecule inositiol polyphosphate regulates some of these enzymes -- presumably by binding to the enzymes and changing their activity.
In the new research, O'Shea and colleagues identified a defective gene, known as ARG82, in budding yeast mutants. They showed that the gene encodes a protein that helps make inositol polyphosphate in the cell nucleus. In yeast lacking this gene, the normal chromatin restructuring of another gene is impaired, they found, and as a result, the ATP-dependent remodeling enzymes do not get "recruited" to the appropriate part of the gene.
The scientists suggest that the ability of inositol polyphosphate to affect the action of a large number of genes may allow organisms to respond quickly and "globally" to environmental change or stress:
"It is possible that the levels or ratios of inositol polyphosphate are altered under certain physiological conditions and that this change may be used by the cell as a signal for global regulation of …transcription," they conclude.
Lead author on the paper is David J. Steger, PhD, a postdoctoral scientist in O'Shea's lab. Co-authors are Elizabeth S. Haswell, PhD, former graduate student in O'Shea's lab; Susan R. Wente, PhD, professor and chair of cell and developmental biology at Vanderbilt University; and Aimee L. Miller, a postdoctoral fellow in Wente's lab.
The research is funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Steven and Michelle Kirsch Foundation, the David and Lucille Packard Foundation and the Leukemia and Lymphoma Society.
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