POLY-A FUNCTION AND METABOLISM IN SACCHAROMYCES CEREVIS

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How genes are differentially regulated by altering the metabolism of their mature mRNA is a key question in molecular biology. Potential points of regulation include nuclear-cytoplasmic mRNA transport, mRNA stability, and mRNA translational efficiency. The poly(A) tail of mRNA is considered important for each of these processes, yet no clear understanding of poly (A) tail function exists. The long term objective of this work is to analyze the role(s) of poly(A) in mRNA metabolism and to understand how modifications in it or the protein bound to it, the poly(A)-binding protein, can affect this metabolism. With this understanding, potential alterations of poly(A)-dependent steps in mRNa metabolism resulting from cellular infection or transformation can be studied. The initial objective of the work is to characterize genes in Saccharomyces cerevisiae which affect poly(A) synthesis, packaging, and degradation. These include genes encoding a poly(A)-polymerase, the poly(A)-binding protein, and seven genes (spbl-spb7) which when mutated allow the cells to live without the essential poly(A)-binding protein. One of these, SPB2, encodes the ribosomal protein L46, and another, SPB4, encodes a protein which is highly homologous to eucaryotic initiation factor 4a and is probably an RNA-helicase. The effects of mutations in these genes on in vivo mRNA transport, poly(A) and mRNA stability, and mRNA translation will be examined. An in vitro poly(A)-degradation assay that faithfully reproduces the in vivo effects of these mutations will be developed. This assay will detect the functional interactions between the poly(A) tail and the remainder of the mRNA, and it will be a model system for studying messenger ribonucleoprotein structure and its affects on mRNA stability. GRANT= R13GM43155 Funds are requested to support travel of participants to the "Metals in Biology" Gordon Research Conference to be held January 22-26, 1990, in Ventura, California. This multidisciplinary conference is thought by many to be the premier small meeting covering the fields of metallobiochemistry and bioinorganic chemistry. Evolving from a FASEB-sponsored meeting on Biological Aspects of Metal-Binding held in 1960, the first Gordon Conference on the subject was convened in 1962 and has been held regularly since then. The meetings have been a forum for the presentation and discussion of the forefront research covering all aspects of the roles of metal ions in biology, biochemistry, and medicine. The popularity of this meeting led to such heavy over-subscription, with large numbers of qualified scientists denied acceptance, that the scheduling was switched to an annual calendar effective January 1987. The topics to be emphasized at the coming meeting include (1) Metalloenzymes with Redox-Active organic Cofactors; (2) DNA-Related Metallobiochemistry; (3) Design of Functional Models for Metalloenzymes; (4) Metalloenzymes of Pharmaceutical Interest; and (5) Manganese in Biology. The format of this conference provides 23 formal presentations by invited speakers, selected short talks on very recent results of significance, and three general poster sessions. Extensive discussion periods are planned for each of the components.