Eukaryotic mRNA can be controlled at many different steps. In the nucleus, transcription and mRNA processing are needed to generate mRNAs that can be translated. In the cytoplasm, mature mRNAs can be regulated at the levels of stability, translation and localization. The objective of the proposed work is to understand the molecular mechanisms that regulate mature mRNAs in animal cells. We focus on controls mediated by sequences that lie beyond the termination codon ? in the 3' untranslated region (3'UTR) and the poly(A) tail. Regulated changes in poly(A) length occur throughout development, affect the translation and stability of many mRNAs, and occur in many species: We concentrate on a family of novel cytoplasmic poly(A) polymerases, called the GLD-2 family. Members of this family, as well as the proteins with which they interact, are conserved among species, and are critical in a wide range of biological contexts ? stem cells, early development and memory, for example. Our ultimate goals are to understand, in molecular terms, how these proteins control the fate and function of mature mRNAs. In the next grant period, we will focus on how GLD-2 PAP acts and is controlled. We continue to emphasize work in Xenopus and early development, and extend our analysis of links between other regulators and GLD-2. We will continue to combine molecular genetics and biochemistry to dissect how GLD-2 and its protein partners function. The broad conservation of these proteins among metazoa, and their presence in most somatic tissues, suggests that our findings will bear broadly on regulation in diverse systems. In focusing sharply on the GLD-2 family, and a few selected biological contexts, we hope to address the broad questions of how 3'UTR controls function, evolve, and coordinate expression of multiple mRNAs.
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