Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease.
Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
Masutani
M
M
Biochemistry Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Tokyo 104-0045, Japan. mmasutan@gan2.res.ncc.go.jp
Nakagama
H
H
Sugimura
T
T
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism*; D016923:Cell Death; D004260:DNA Repair; D004791:Enzyme Inhibitors / Q000494:pharmacology; D042822:Genomic Instability; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D015533:Transcriptional Activation
D004791:Enzyme Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase