Studies on the Role of Poly (ADP-ribosyl) Action in Cell Differentiation and Oncogenesis

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1. Cloning of cDNA coding for poly (ADP-ribose) synthetase : A complete amino acid sequence of bovine poly (ADP-ribose) synthetase was determined by cDNA cloning. A comparison of the sequence with those of human and mouse enzymes revealed that various structural units (e. g., Zn-binding fingers) important to enzymatic functions such as DNA-binding, automodification, and NAD-binding have been almost completely conserved throughout evolution. For the use of homology analysis at levels of regions or domains, we invented a new plot termed "homology profile".2. Discovery of specific inhibitors of poly (ADP-ribosyl) action : From among 300 compounds tested, we found a number of potent inhibitors of poly (ADP-ribose) synthetase, including 1,8-naphthalimide, 6 (5H) -phenanthridinone, 1-hydroxyisoquinoline, their derivatives, and 4-hydroxyquinazoline ; theywee more potent and specific than known inhibitors such as nicotinamide and benzamide derivatives. We also found that vitamin K as well as novobiocin was much more specific for mono- than poly (ADP-ribosyl) action.3. Induction of tumor cell differentiation : We succeeded in inducing differentiation of teratocarcinoma cells in culture by administrating our new inhibitors of poly (ADP-ribosyl) ation, such as 4-hydroxyquinazoline and arachidonic acid.