Poly(ADP-ribose): PARadigms and PARadoxes

摘要: Poly(ADP-ribosyl)ation (PARylation) is a posttranslational protein modification (PTM) catalyzed by members of the poly(ADP-ribose) polymerase (PARP) enzyme family. PARPs use NAD(+) as substrate and upon cleaving off nicotinamide they transfer ADP-ribosyl moiety covalently to suitable acceptor proteins elongate chain adding further ADP-ribose units create branched polymer, termed (PAR), which rapidly degraded glycohydrolase (PARG) ADP-ribosylhydrolase 3 (ARH3). In recent years several key discoveries changed way we look at biological roles mode operation PARylation. These paradigm shifts include but are not limited (1) single PARP expanding family; (2) DNA-break dependent activation extended other DNA independent PARP-activation mechanisms; (3) one molecular mechanism (covalent PARylation target proteins) underlying effect now complemented mechanisms such protein-protein interactions, PAR signaling, modulation pools (4) principal role in damage sensing expanded numerous, diverse functions identifying PARP-1 real moonlighting protein. Here review most important research also highlight some many controversial issues (or paradoxes) field mostly synergistic antagonistic effects PARG; mitochondrial decomposition, cross-talk between signaling pathways (protein kinases, phosphatases, calcium) divergent PARP/PARylation longevity age-related diseases.