PHILADELPHIA – Genomes throughout the animal kingdom and beyond are characterized by extensive segments that are inactive, lengthy stretches of DNA containing multiple genes that are closed to gene transcription. Scientists believe one reason for this broad gene silencing is the vital need for genomic stability, for protection against unwanted recombinations of genetic material or other disruptions of the genome's integrity.
Genomic instability, particularly in the regions at the ends of the chromosomes known as telomeres, has been linked to aging in humans and an elevated risk for aging-related diseases, the most prominent of which is cancer. For this reason, insights into the mechanisms of gene silencing could provide important guideposts for new approaches to retarding aging or treating cancer.
Now, an investigation led by researchers at The Wistar Institute has shown that an enzyme known as Ubp10 plays a vital role in protecting the telomeric regions of the genome from potential destabilizing molecular events. The enzyme helps to keep the genome structurally closed, unavailable for transcription and possibly protected from dangerous genetic recombinations with other regions of the genome. A report on the research, which was conducted in yeast, appears in the February 18 issue of Molecular Cell.
"There are regions of the genome that have to be inaccessible," says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor in the gene expression and regulation program at Wistar and senior author on the study. "Otherwise, they can recombine with themselves or with other DNA segments. In the telomeres, such events may accelerate aging or trigger cancer in humans."
"We have identified a molecular mechanism to explain how this enzyme helps keep telomeric DNA silenced and potentially protects the genome from destabilizing activity," says N.C. Tolga Emre, a graduate student in Berger's laboratory and lead author on the study.
The Ubp10 enzyme acts on histones, molecules that have attracted increasing attention from scientists as they move beyond sequencing the human genome to trying to better understand how DNA is managed and its activity regulated. Histones are small proteins around which DNA is coiled to create structures called nucleosomes. Compact strings of nucleosomes, then, form into chromatin, the substructure of chromosomes. In many cases, when the DNA is tightly wrapped around the histones, the genes cannot be accessed and their expression is repressed. When the coils of DNA around the histones are loosened or the histone molecules are altered, the genes become available for expression.
It is the complex activity governing this process to which Ubp10 contributes. Enzymatic modifications to histones control DNA activation or silencing through the addition or removal of acetyl, methyl, and ubiquitin molecules in prescribed sequences and patterns. One job of Ubp10, as identified in this study, is to remove ubiquitin from certain histones where ubiquitin is associated with gene activation and to maintain low levels of the ubiquitin molecule at those sites.
Interestingly, Ubp10 appears to work similarly and in concert with another enzyme called Sir2, which removes acetyl molecules from histones. Sir2 has also been associated with promoting genomic stability, and some studies have linked it intriguingly to the aging process. Some studies, for example, have suggested that low-calorie diets that extend life also boost Sir2 activity dramatically. ###
In addition to lead author Emre and senior author Berger, the other Wistar-based co-authors on the Molecular Cell study are Kristin Ingvarsdottir, Anastasia Wyce, Karl Henry, Ph.D. (now at Drexel University College of Medicine), and Keqin Li. Ronen Marmorstein, Ph.D., a professor in the gene expression and regulation program at Wistar, is also a co-author. Additional co-authors include Adam Wood and Ali Shilatifard at St. Louis University and Nevan J. Krogan and Jack F. Greenblatt with the University of Toronto. Primary funding for the study was provided by the National Institutes of Health, with additional support from the American Cancer Society, the Mallinckrodt Foundation, the Canadian Institutes of Health Research, the Ontario Genomics Institute, and the National Cancer Institute of Canada with funds from the Canadian Cancer Society.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center focused on basic and translational research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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