Date of Award

6-1985

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. J. R. Smiley

Abstract

Herpes Simplex Virus DNA displays a number of unusual features which have been the subject of intense scrutiny in a number of laboratories. The genome is composed of two segments, each of which is flanked by inverted repeats. These segments invert freely with respect to each other generating equisolar quantities of four different isomers. This phenomenon, called segment inversion, was reputed to be the result of a site specific recombination mechanism operating on the terminal repeat, the 'a' sequence, which is part of the inverted repeats flanking each segment. The 'a' sequence was also implicated as the cleavage/packaging signal utilized by the virus to process viral DNA concatemers. The underlying mechanism of this process was believed to be a double strand break at a specific site between two 'a' sequences. The models of HSV maturation were deficient, however, in explaining several phenomena, namely the tendency of the 'a' sequence to accumulate tandem iterations of itself, the asymmetric distribution of these tandem iterations to one end of the genome, but not to the other, and the ability of defective genomes, which do not have tandemly iterated 'a' sequences, at least initially, to be efficiently packaged. I have shown that the "a" sequence actually contains two signals for cleavage/packaging, not one, that the cleavage occurs it specific distances from these signals, not in specific sequences, and that the cleavage mechanism results in a duplication of the cleavage signal and flanking DNA. Furthermore, I have determined that the 'a' sequence is not a target for site specific recombination, and that there is better evidence to support the idea that segment inversion is accomplished by a number of related, but independent mechanisms, including generalized recombination.

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