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Molecular Biology Basis for the Response of Poly (ADP-RIB) Polymerase and NAD Metabolism to DNA Damage Caused by Mustard Alkylating Agents

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Midterm rept. 16 Jun 1987-1 Aug 1988

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During the midterm of this contract we have performed a variety of experiments to provide a strategy to modulate the nuclear enzyme poly ADP- ribose polymerase, in cultured keratinocytes. This enzyme modifies a variety of nuclear proteins utilizing NAD. DNA is required for the catalytic activity of the enzyme and the activity is dependent upon the presence of strand breaks in this DNA. It has been hypothesized that human skin exposed to mustards may develop blisters due to a generalized lowering of NAD in exposed skin cells. Furthermore, one mechanism may be the production of DNA strand breaks in skin cells by mustards which activate NAD depletion in these cells via the polyADP- ribose polymerase reaction as described above. During the midterm we have cloned various regions of the cDNA for polyADP-ribose polymerase into a series of retroviral expression vectors. We have shown that when keratinocytes are transfected with such expression vectors, increased amounts of polyADP-ribose polymerase mRNA and protein are expressed. The projects are currently exploring the use of a new retroviral system N2 which offers several advantages over the retroviral expression system system used earlier. Retroviral expression vectors should allow us to modulate the activity of this nuclear enzyme in a variety of skin cells in vitro. and in vivo. Keywords RA V Human tissue Skin Lab animals Cell cultures Athymic mice Sulfur mustard PolyADP-Ribese.

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  • Biochemistry

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