Accession Number:

ADA416654

Title:

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

Descriptive Note:

Annual rept. 1 May 2002-30 Apr 2003

Corporate Author:

GEORGETOWN UNIV WASHINGTON DC

Personal Author(s):

Report Date:

2003-05-01

Pagination or Media Count:

31.0

Abstract:

PARP is a chromatin bound enzyme, which is pivotal in the recovery of cells from DNA strand break damage. SM confers damage to cells causing DNA strand breaks. In collaboration with intramural scientists of USAMRICD, we recently demonstrated that SM, in part, causes cellular pathology and death via initiating apoptosis, and in primary PARP fibroblasts by causing such an extensive depletion of ATP and NAD that the skin cells die by necrosis. Given that the mitochondria is a potential target of SM toxicity via release of cytochrome-c leading to activation of the downstream caspase cascade, most emphasis during year one has focused on the changes that occur in mitochondria following exposure to SM. We are also determining the role of PARP in SM- induced necrosis and apoptosis and why this response is cell-type specific. SM induces apoptosis in both wild type and PARP-- keratinocytes, and apoptosis in PAkP-- fibroblasts, thus, we will determine the targets in the apoptotic cascade upstream. Proteins and biological systems to be surveyed include the Bcl-2 family p53 depletion of NADATP levels table transfection of a mutant PARP cDNA catalytically inactive chromatin and nuclear structure ultrastructure during early apoptosis. We anticipate also using our PARP KO mice. Given that PARP-- fibroblasts undergo SM-induce apoptosis, we will test whether there is also an initial decrease in the NADATP levels in PARP-- fibroblasts after exposure to SM, possibly due to other genes in the PARP family.

Subject Categories:

  • Biochemistry
  • Polymer Chemistry
  • Chemical, Biological and Radiological Warfare

Distribution Statement:

APPROVED FOR PUBLIC RELEASE