Accession Number : ADA319494

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

Descriptive Note : Midterm rept.,

Corporate Author : GEORGETOWN UNIV WASHINGTON DC

Personal Author(s) : Smulson, Mark E.

PDF Url : ADA319494

Report Date : JUL 1996

Pagination or Media Count : 34

Abstract : During the course of this contract, we have performed a variety of experiments to provide a strategy to modulate the nuclear enzyme poly(ADP-ribose) polymerase (PARP), 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. During the contract period, we have established a stably transfected human keratinocyte cell line which expresses antisense transcripts to PARP mRNA when these keratinocyte were grafted onto nude mice they formed histologically normal human skin. Accordingly, a model system has been developed in which the levels of PARP can be selectively manipulated in human keratinocytes in reconstituted epidermis as well. We also showed that PARP was proteolytically cleaved at the onset of spontaneous apoptosis following proteolytic conversion of CPP32b to its active form, termed 'apopain'. Having characterized the events associated with apoptosis, we determined, during the last period, whether any or all of these features could be observed following exposure of keratinocytes to SM.

Descriptors :   *DEOXYRIBONUCLEIC ACIDS, *CHEMICAL AGENTS, *ALKYLATION, *MUSTARD AGENTS, HUMANS, ENZYMES, METABOLISM, CATALYSTS, EXPOSURE(PHYSIOLOGY), MICE, CELLS(BIOLOGY), SKIN(ANATOMY).

Subject Categories : Chemical, Biological and Radiological Warfare

Distribution Statement : APPROVED FOR PUBLIC RELEASE