Physiology and pathophysiology of poly(ADP-ribosyl)ation

One of the immediate eukaryotic cellular responses to DNA breakage is the c ovalent post-translational modification of nuclear proteins with poly(ADP-r ibose) from NAD(+) as precursor, mostly catalysed by poly(ADP-ribose) polym erase-1 (PARP-1). Recently several other polypeptides have been shown to ca talyse poly(ADP-ribose) formation. Poly(ADP-ribosyl)ation is involved in a variety of physiological and pathophysiological phenomena. Physiological fu nctions include its participation in DNA-base excision repair, DNA-damage s ignalling, regulation of genomic stability, and regulation of transcription and proteasomal function, supporting the previously observed correlation o f cellular poly(ADP-ribosyl)ation capacity with mammalian life. The pathoph ysiology effects are mediated through PARP-1 overactivity, which can cause cell suicide by NAD(+) depletion. It is apparent that the latter effect und erlies the pathogenesis of a wide range of disease states including type-1 diabetes, ischaemic infarcts in various organs, and septic or haemorrhagic shock. Therefore pharmacological modulation of poly(ADP-ribosyl)ation may p rove to be an exciting option for various highly prevalent, disabling and e ven lethal diseases. (C) 2001 John Wiley & Sons, Inc.