Abstract
Poly(ADP-ribosyl)-ation is a nonprotein posttranslational modification of proteins and plays an integral part in cell physiology and pathology. The metabolism of poly(ADP-ribose) (PAR) is regulated by its synthesis by poly(ADP-ribose) polymerases (PARPs) and on the catabolic side by poly(ADP-ribose) glycohydrolase (PARG). PARPs convert NAD+ molecules into PAR chains that interact covalently or noncovalently with target proteins and thereby modify their structure and functions. PAR synthesis is activated when PARP1 and PARP2 bind to DNA breaks and these two enzymes account for almost all PAR formation after genotoxic stress. PARG cleaves PAR molecules into free PAR and finally ADP-ribose (ADPR) moieties, both acting as messengers in cellular stress signaling. In this review, we discuss the potential of RNAi to manipulate the levels of PARPs and PARG, and consequently those of PAR and ADPR, and compare the results with those obtained after genetic or chemical disruption.
Highlights
Chemical Inhibition of PAR Metabolizing EnzymesWithin the last few decades, the concept of interfering with proteins involved in DNA repair and stress signaling has attracted a lot of attention in both basic and clinical research
Poly(ADP-ribosyl)-ation is a nonprotein posttranslational modification of proteins and plays an integral part in cell physiology and pathology
PARP1 in processing genotoxic attacks. Both authors concluded that the lack of the Parp1 gene led to an impaired DNA repair capacity, an accumulation of DNA strand breaks and, subsequently, high genomic instability
Summary
Within the last few decades, the concept of interfering with proteins involved in DNA repair and stress signaling has attracted a lot of attention in both basic and clinical research. [51±53], and 3,4-Dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) [54±57], were extensively used to suppress PARP activity in vitro, in cells and animals (Figure 2) They share the potential to interfere with both PAR-synthesizing enzymes activated by DNA damage due to the homology in the catalytic domain of PARP1 and PARP2, albeit with different kinetics. To overcome this problem, Moroni and co-workers developed a set of specific PARP2 inhibitors [58]. Beside synthetic PARP inhibitors, a panel of naturally occurring molecules was discovered that have PARPsuppressing activity These compounds cover such different chemical structures as tryptophan derivatives, purines, xanthins, vitamins, hormones and metals [59]. Adenosine 5'-diphosphate (hydroxymethyl) pyrrolidinediol (Z)-3-(5-(5-Bromo-1-(2,6-dichlorobenzyl)-2-oxoindolin-3-ylidene)-4-oxo-2-thioxothiazo-lidin-3-yl) propanoic acid
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
