POLY(ADP-RIBOSYL)ATION, DNA STRAND BREAKS, CHROMATIN AND CANCER

Studies on poly(ADP-ribosyl)ation related to chromatin structure and to nuclear functions such as repair, gene expression and replication are reviewed. Poly(ADP-ribosyl)ation might be involved in regulating the activity of nuclear enzymes involved in the metabolism of DNA strand breaks such as ligase II and topoisomerases I and II. In addition, it modifies nuclear proteins participating in gene expression including HMG non-histones, large T antigen, acetylated histone H4 and nuclear matrix proteins. It is speculated that poly(ADP-ribose) can induce free DNA domains by removing histones from specific nucleosomes whose DNA has been damaged. This process is proposed to require specific proteins recognizing lesions on DNA that ultimately attach the damaged site on the nuclear matrix where the repair enzymes are located. The role of poly(ADP-ribosyl)ation in carcinogenesis arises from that inhibitors of this modification potentiate the cytotoxicity of DNA-damaging drugs used in cancer chemotherapy and either enhance or inhibit tumor growth.