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Recent evidence obtained with transgenic knockout mice suggests that the enzyme poly(ADP-ribose)polymerase (PARP) does not play a direct role in DNA break processing [1, 2]. Nevertheless, inactivation of the catalytic or the DNA nick-binding functions of PARP affects cellular responses to genotoxins at the level of cell survival, sister chromatid exchanges and apoptosis [2, 3]. In the present report, we conceptualize the idea that PARP is part of a DNA break signal mechanism [4, 5]. In vitro screening studies revealed the existence of a protein family containing a polymer-binding motif of about 22 amino acids. This motif is present in p53 protein as well as in MARCKS, a protein involved in the regulation of the actin cytoskeleton. Biochemical analyses showed that these sequences are directly targeted by PARP-associated polymers in vitro, and this alters several molecular functions of p53- and MARCKS protein. PARP-deficient knockout mice from transgenic mice were found to exhibit several phenotypic features compatible with altered DNA damage signaling, such as downregulation and lack of responsiveness of p53 protein to genotoxins, and morphological changes compatible with MARCKS-related cytoskeletal dysfunction. The knockout phenotype could be rescued by stable expression of the PARP gene. - We propose that PARP-associated polymers may recruit signal proteins to sites of DNA breakage and reprogram their functions. [ABSTRACT FROM AUTHOR]

The enzymes poly(ADP-ribose)polymerase and poly(ADP-ribose) glycohydrolase may cooperate to drive a histone shuttle mechanism in chromatin. The mechanism is triggered by binding of the N-terminal zinc-finger domain of the polymerase to DNA strand breaks, which activates the catalytic activities residing in the C-terminal domain. The polymerase converts into a protein carrying multiple ADP-ribose polymers which displace histones from DNA by specifically targeting the histone tails responsible for DNA condensation. As a result, the domains surrounding DNA strand breaks become accessible to other proteins. Poly(ADP0ribose) glycohydrolase attacks ADP-ribose polymers in a specific order and thereby releases histones for reassociation with DNA. Increasing evidence from different model systems suggests that histone shuttling participates in DNA repair in vivo as a catalyst for nucleosomal unfolding. [ABSTRACT FROM AUTHOR]

Culture and differentiation parameters of a human thyroid transformed cell line (HuT) were analyzed. Treatment with high concentrations of chemical agents namely dimethyl sulphoxide and retinoic acid, exerted a dramatic cytotoxic effect. The exposure of these cells to the lowest doses of retinoic acid as well as to 8 mM-16 mM 3-aminobenzamide a potent inhibitor of poly(ADPribose)polymerase, resulted in a delay of cell proliferation. Poly(ADPribose)polymerase activity was differently affected by retinoic acid (stimulation) and 3-aminobenzamide (inhibition). [ABSTRACT FROM AUTHOR]