The Molecular Toxicology of Chromatin [report]

E. Kun
1983 unpublished
DTIC i ELECTE UEG 6 1983,.. Ã Controlling Office: Air Force Office of Scientific Research/NI Bolling Air force Base, DC 20332 ... J Li.. Approved for publto releaseg C-83 12 06 1 34 distributionun"limited. 20. ABSTRACT (Co.'ur.. an roveree .*1 anocoew mE Ideuvlf by Weock mwelow) M. The chemical (macromolecular) structure and biological function of the eukaryotic cell specific nuclear polymer: polyadenosine diphosphoribose has been Investigated In specific cell nuclei isolated from animals
more » ... and from human fibroblast cultures. This polymer Is formed enzymatically from MAD In eukaryotic nuclei. The polymer was Identified for the first time, as (CONTINUED ON OTHER SIDE....) DO ~~S 173 DITONOF NO S5S OSOLTE SECURITY CLASSIFICATION OFTIS PAGE (Whomn Date gntP01 SCUMITY CLASF NAT000 OF THIS PA@E(WhM Dfte Znatru item 20. (Continued) a unique nucleic acid structure which can form helix-helix type non-covalent association between long chain polymers that are on one end covalently bound to non hIstone proteins, comprising a supramolecular DNA structure associated network system. The influence of differentiation determined by essays in different call types within one organ and effects of developmental hormones in animals on polyadenosine diphosphoribosylation and the role of the polymer in cell transformation in cell cultures has been studied by focusing on the quantitative and qualitative changes of non histone proteinpolyadenosine diphosphoribose adducts in chromatin under controlled experimental conditions. A positive correlation was found between changes (inhibition) in rates of polyadenosine diphosphoribosylation and cellular hypertrophy of cells incapable of DNA synthesis Indicating a physiologic control function of the polymer-protein network system in DNA template activity in these cells. It is apparent therefore that the role of poly ADP-ribosylation is different In cells that do not divide as compared to cells with mitotic potential. In cell cultures an S phase specific regulatory role of poly ADP-ribosylation has been identified. Under physiological conditions DKA and poly(ADP-ribose) syntheses run parallel in physiologically functioning cells. When a non toxic but transforming dose of an ultimate carcinogen acts in the S phase the two synthetic functions are uncoupled, and a carcinogen depresses poly AD-ribosylation, presumably allowing the expression of carcinogen modified DNA sequences (oncogenes?). This dissociation of structural control of DNA by poly ADP-ribosylation can be completely restored by non toxic trace quantities of molecules which at higher concentrations are recognized as Inhibitors of poly(ADP-ribose) polymeras (presumably acting as enzyme inducers at low levels). On the basis of these results: a) a new area of gene-expression control has been Identified and; b) a biochemical approach to the prevention of environmental chromatin poisoning (by carcinogens, UV or ionizing radiation) became feasible. UNCLASSIFIED .SBCuHITY CL CA ?IOi 01 ?M.
doi:10.21236/ada135399 fatcat:gwruunf2vrcn5gcafx6zhltms4