Regulatory mechanisms of poly(ADP-ribose)polymerase

Here, we describe the latest developments on the mechanistic characterizati on of poly(ADP-ribose) polymerase (PARP) [EC 2.4.2.30], a DNA-dependent enz yme that catalyzes the synthesis of protein-bound ADP-ribose polymers in eu caryotic chromatin. A detailed kinetic analysis of the automodification rea ction of PARP in the presence of nicked dsDNA indicates that protein-poly(A DP-ribosyl)ation probably occurs via a sequential mechanism since enzyme-bo und ADP-ribose chains are not reaction intermediates. The multiple enzymati c activities catalyzed by PARP (initiation, elongation, branching and self- modification) are the subject of a very complex regulatory mechanism that m ay involve allosterism. For instance, while the NAD(+) concentration determ ines the average ADP-ribose polymer size (polymerization reaction), the fre quency of DNA strand breaks determines the total number of ADP-ribose chain s synthesized (initiation reaction). A general discussion of some of the me chanisms that regulate these multiple catalytic activities of PARP is prese nted below.