Claire Moore, Ph.D.
Tufts University School of Medicine
Regulating the stress response by targeting mRNA polyadenylation factors
The goal of our research is to understand the molecular mechanisms of mRNA polyadenylation, its regulation in response to changes in cell state and environmental conditions, and its coordination with other nuclear processes such as transcription, mRNA export, and DNA damage repair. Polyadenylation is an essential maturation step in which mRNA precursor is trimmed at its 3’ end and a poly(A) tail added. Our work has led to the identification and functional analysis of many components of the 20-subunit processing complex, the demonstration of its regulation by post-translational modifications, and the characterization of novel ways in which it interfaces with transcription, mRNA export and mRNA quality control. We have taken advantage of yeast as an easily manipulated model organism to study this complicated process, and are using this model to understand how changes in the polyadenylation machinery help the cell adapt to stress and to shift energy production from fermentation to mitochondrial respiration when glucose supplies are depleted.
The poly(A) site position will vary with the differentiated state of a cell in a process called alternative polyadenylation (APA), yielding mRNA isoforms with different lengths of 3’ untranslated (3’ UTRs) or coding regions. About 70% of human genes have multiple poly(A) sites, highlighting the potential for APA to diversify the transcriptome. APA has an increasingly appreciated role in regulation of gene expression, as 3’ UTR shortening removes binding sites for factors such as miRNAs that influence mRNA stability, translation, and subcellular localization, while coding region shortening alters protein function. However, how APA is achieved at a molecular level remains poorly understood. New projects in the lab use mammalian cell culture models to address questions such as how alternative polyadenylation facilitates the differentiation of liver cells, adipocytes, and macrophage and how epigenetic factors alter poly(A) site selection in cancer cells.
My talk will focus on Ipa1, a novel regulator of polyadenylation that specifically targets the endonuclease that cuts at the poly(A) site and protects it from ubiquitin-mediated proteosomal degradation. Our findings suggest that regulation of Ipa1 activity controls the expression of genes needed for mitochondrial function and helps the cell cope with changes in nutrient availability. I will also present our findings on an unexpected role for the conserved Pcf11 polyadenylation factor in the transcription and mRNA stability of transcripts regulated by the general response to environmental stress. These studies have been done in collaboration with Dr. Joel Graber, at MDIBL.