New Scholar Award in Aging
Danesh Moazed, Ph.D.
Harvard Medical School

Connections Between the Nucleolus and Cellular Aging

Chromosomes, the carriers of the cell's genetic information, are composed of distinct functional domains that ensure their fateful inheritance during the process of cell division and chromosome duplication. One example of such functional organization is the presence of large stretches of DNA which are packaged into a repressed state where gene expression is silenced. Silencing of DNA domains is observed in a broad spectrum of organisms ranging from unicellular eukaryotes like yeast to complex multicellular organisms like us and appears to play a fundamental role in regulating chromosome behavior. For example, silencing has been shown to play a crucial role in both regulating gene expression and maintaining chromosome stability.

Studies of cellular aging in yeast have revealed a direct connection between life span and silencing in this organism. Loss of silencing at the chromosome locus that contains the genes for ribosomal RNA (components of cellular machines that synthesize protein) results in instability of this chromosome region. To make enough ribosomal RNA to sustain their rapid growth rate, cells need many copies of the genes that encode these RNAs. These genes, called rDNA, exist at about 150 tandem copies on one of the yeast chromosomes. This high copy number results in instability due to natural genetic exchange that occurs between identical DNA sequences. A byproduct of such DNA exchange events is the separation of DNA in the form of circles from the rest of the chromosome. Such separation removes the DNA from regulatory mechanisms that govern chromosome duplication and inheritance in the cell. The DNA circles can therefore duplicate and accumulate to very high numbers and cause cell death. By repressing genetic exchange between rDNA sequences, silencing slows the rate of accumulation of run away DNA circles and thereby slows cellular aging.

Our lab works on the factors that are responsible for packaging DNA into a silent state. In particular, we have identified a complex of proteins that acts specifically at the repetitive rDNA region. We have recently discovered that the Sir2 protein, a universally conserved component of the rDNA-silencing complex, possess an enzymatic activity that is essential for all gene silencing. Sir2 appears to covalently modify itself and other chromatin components in a step that is required for making DNA silent. The broad conservation of Sir2-like proteins suggests that Sir2-based silencing mechanisms also exist in human cells.

Contact Dr. Moazed.