Adenovirus messenger RNA synthesis is potentially controlled at several levels: (i) Positive and negative regulation of the RNA initiation step; (ii) Transcription termination vs antitermination; (iii) Selection of 3' poly A site for mRNA; (iv) Differential splicing of nuclear precursors; (v) Changes in mRNA stablity. The major event in Ad-2 gene expression is the early-late switch which activates abundant mRNA synthesis from the major late transcription unit resulting in the expression of 10-20 late specific viral genes. The switch is made possible by a complex early period which prepares the cell for viral DNA replication and late gene expression. Despite great interest, little is known of the biochemical or molecular basis for the mechanisms which control Ad-2 gene expression. We therefore propose: 1) To identify specific RNA transcription and processing steps which are controlled during the early stage of infection, and the early-late transition. We shall introduce drug or mutant blocks during the early phase, and identify those steps which are coordinately inhibited, or permitted by the block. 2) To analyze in detail the mechanisms of activation of the late transcription unit, and the pathway of processing of late transcripts. 3) To analyze the structures of nuclear RNA-protein complexes which function in late RNA processing.
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