Physiology and pathophysiology of poly(ADP-ribosyl)ation.
One of the immediate eukaryotic cellular responses to DNA breakage is the covalent post-translational modification of nuclear proteins with poly(ADP-ribose) from NAD+ as precursor, mostly catalysed by poly(ADP-ribose) polymerase-1 (PARP-1). Recently several other polypeptides have been shown to catalyse poly(ADP-ribose) formation. Poly(ADP-ribosyl)ation is involved in a variety of physiological and pathophysiological phenomena. Physiological functions include its participation in DNA-base excision repair, DNA-damage signalling, regulation of genomic stability, and regulation of transcription and proteasomal function, supporting the previously observed correlation of cellular poly(ADP-ribosyl)ation capacity with mammalian life. The pathophysiology effects are mediated through PARP-1 overactivity, which can cause cell suicide by NAD+ depletion. It is apparent that the latter effect underlies 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 prove to be an exciting option for various highly prevalent, disabling and even lethal diseases.
Bürkle
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Department of Gerontology, Institute for Ageing and Health, University of Newcastle, Newcastle upon Tyne, NE4 6BE, UK. Alexander.Buerkle@ncl.ac.uk
D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D007238:Infarction / Q000201:enzymology / Q000503:physiopathology; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000235:genetics; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014158:Transcription, Genetic
D009097:Multienzyme Complexes; D011064:Poly Adenosine Diphosphate Ribose; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex