ABSTRACT
Poly-ADP-ribosylation (PAR) is a posttranslational modification of proteins. The process was discovered and reported in early 1960s by Mandel and coworkers [1,2]. Since then it has been a subject of extensive research [reviewed in Refs. 3-5]. The interest has endured because of the uniqueness associated with PAR metabolism and its continuously expanding biological involvement, implications, and roles. The ubiquitous, enzyme catalyzed, fully reversible metabolic reaction involves transfer of an ADP-ribose moiety from a metabolic donor, nicotinamide adenine dinucleotide (NADþ), to acceptor amino acid residues of a target protein. The primary biosynthesizing enzyme for PAR reaction is poly-ADP-ribose polymerase (PARP). The commonly modified amino acid residues in eukaryotes are glutamate and aspartate, though occasionally ADP-ribose moiety is found on residues such as arginine, cystine, asparagine, and diphthamide [3]. The target proteins for PAR are mostly nuclear and include, but are not limited to, such diverse array of proteins as histones, endonucleases, DNA pol a and b, DNA ligase I and II, topoisomerase I and II, RNA polymerases, reverse transcriptase, high mobility group (HMG) proteins, p53, Fos, AP endonuclease, Ku70, and the enzyme responsible for biosynthesis of PAR, that is, PARP itself. The metabolic reaction creates a complex, variably sized, and covalently attached homopolymeric, heterogeneous branched or unbranched ADP-ribose polymer adducts on the target protein thereby accomplishing the posttranslational modification of a protein (Figure 15.1). The complex homopolymeric ADP-ribose polymer adducts may contain up to 200 or, occasionally, more of monomers of ADP-ribose in linear or multiple branching architecture. Simultaneously, the main biodegrading enzyme of ADP-ribose polymer, the poly-ADP-ribose glycohydrolase (PARG), acts on the homopolymer attached to a modified protein and rapidly de-poly-ADP-ribosylates it by randomly and sequentially degrading the ADP-ribose monomers from the target protein (Figure 15.1). The two metabolic reactions occur simultaneously but in
FI G U R E 15 .1
