PolyADP-ribosylation and Cancer

in Japanese

PolyADP-ribosylation reaction modifies acceptor proteins, using NAD as a substrate, with ADP-ribose residues sequentically conjugated. The length of poly(ADP-ribose) becomes more than hundred residues and regulates protein functions dynamically. Poly(ADP-ribose) is discovered in 1960s by three research groups including National Cancer Center(Biochim. Biophys. Acta., 138:438-441). Seventeen members of poly(ADP-ribose) polymerase (Parp) family proteins are identified. Among them, Parp-1 has a dominant activity and is activated mainly in nuclei. Parp-1 catalyzes polyADP-ribosylation of proteins including Parp-1 itself and histone. Synthesized poly(ADP-ribose) is mainly degraded by poly(ADP-ribose) glycohydrolase (Parg). PolyADP-ribosylation reaction is involved in DNA repair, genomic stability, cell death regulation and differentiation control. Functional significance of polyADP-ribosylation reaction in carcinogenesis and cancer treatment is being studied using genetically modified mouse models and biochemical and molecular biological approaches. (Genes Chromosomes Cancer, 2003, 38:339-348, Cell. Mol. Life Sci., 2005, 62:769-783).
Poly(ADP-ribose) metabolism in vivo is also being investigated after treatment with DNA damaging agents. Basic study on the development of therapeutic agents of cancer, which targets polyADP-ribosylation reaction is also undertaken.

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