The Molecular Biological Basis for the Response of Poly (ADP-RIB) Polymerase and NAD Metabolism to DNA Damage Caused by Mustard Alkylating Agents
Abstract
Poly(ADP-ribose) polymerase (PARP), 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/ATD in exposed skin cells. We have now utilized primary dermal fibroblasts, immortalized fibroblasts, and keratinocytes derived from PARP 4-and their wild type littermates (PARP +1+) and mice to determine the contribution of PARP to SM toxicity. Primary skin fibroblasts from PARP- deficient mice demonstrated increased caspase-3 activity, compared to those from PARP +/+ animals. Propidium Iodide staining and PARP cleavage patterns revealed a SM dose-dependent increase in necrosis in PARP +1+, but not PARP 4- cells. Using immortalized PARP -I- keratinocytes stably transfected with the human PARP cDNA or control cells, the presence of PARP and its activity, inhibited markers of apoptosis in these cells as well.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2001
- Accession Number
- ADA393356
Entities
People
- Mark E. Smulson
Organizations
- Georgetown University