Michael McAlear: Faculty and Lab Website
Regulated cell growth and division depends heavily upon the biogenesis of ribosomes, those large, essential, complex, and evolutionarily conserved molecular machines that through translation, catalyze the synthesis of new proteins. The importance of ribosomes to human health and disease are numerous, including the observations that ribosomes are the target of many antibiotics, and the fact that defects in ribosome metabolism are associated with the development of some cancers. The metabolic pathways that participate in ribosome biogenesis are elaborate, and together they constitute a large fraction of the total cellular economy. Because the process of ribosome biogenesis is so important to cells, it is tightly regulated in response to changing cellular conditions. One aspect of this regulation lies in the transcriptional control of the genes that function in the ribosome and rRNA biosynthesis (RRB) pathway. There are over 200 RRB genes in budding yeast, and their expression is tightly regulated in response to heat shock, osmotic stress and glucose replenishment. We discovered that a significantly large fraction (i.e. 15%) of these genes – as well as the genes that encode for ribosomal proteins (RPs) – exist on the chromosomes as co-regulated adjacent gene pairs of all possible tandem, convergent or divergent orientations. The immediate, adjacent pairing of related genes was observed across different biochemical pathways in yeast, and also through other eukaryotes including in plants and in animals. We observed that the physical positioning of genes as immediate adjacent pairs was associated with tighter gene co-regulation, higher levels of conservation across related yeast species, and higher overall levels of expression. This phenomenon of adjacent gene co-regulation (AGC) is being investigated by genetic, biochemical and genomic approaches. We are determining what DNA sequence and protein determinants function in the molecular mechanisms that effect AGC. Understanding how adjacent RRB genes are turned on an off in response to varied environmental conditions is important for not only understanding how ribosome biogenesis is regulated, but also as a model system for understanding how cells react to specific stimuli and coordinately regulate the expression of large sets of genes.