CHROMOSOME STRUCTURE

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The two broad goals of this proposal are to learn how the structure of Drosophila chromosomes is encoded in DNA, and to learn what regulatory signals determine the major levels of transcriptional control in Drosophila. The specific areas that relate to structural questions concern encoding the three-dimensional morphology of polytene chromosomes; the relationship between polytene and non-polytene chromosomes; and DNA regions that are necessary for the induction of RNA puffs in polytene chromosomes. The specific areas that relate to transcriptional aspects of chromosome function concern the timing and the nature of the regulatory signals for dosage compensation in Drosophila, and the evolutionary changes that are needed to establish or to lose this compensation; the regulatory signals that are superimposed on RNA puffing signals to result in autonomous transcriptional control of neighboring genes within an inducible puff region; the mechanism of transcriptional inactivation that is conferred by type I inserts in ribosomal RNA genes. Specific DNA sequences to be used for these experiments include ribosomal, satellite, histone, bithorax, heat-shock protein gene 83, and sequences near chromosome regions 47D and 7F. The methodology for achieving these goals includes genetic, cytological, and molecular biological approaches. Germ-line transformation using P-elements will provide a functional assay for resolving questions posed here. There are several health-related aspects of this project; a potential oncogene or regulator of oncogenesis will be studied; the successful induction of polyteny in cells not normally destined for polyteny could lead to the induction of polyteny in mammalian cells, which would be a useful cytogenetic advance; the precocious activation of DNA replication origins appears to be common in Drosophila. This latter phenomenon may be related to initial events of gene amplification that appear to be important in some tumors, and in development of resistance by tumor cells to some chemotherapeutic drugs.