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Cell Division: PARP& PARG Inhibitors | | | Inhibitors | Related Products
Poly(ADP-ribosyl)ation (pADPr) is a covalent posttranslational modification process that occurs during DNA repair, replication, and transcription. It is brought about by poly(ADP-ribose)polymerases (PARP), which are activated by breaks in DNA strands. PARPs are a group of Zn2+-binding multi-functional enzymes that catalyze the transfer of ADP-ribose (ADPr) units onto protein acceptors to produce linear and/or branched polymers of ADPr. Upon binding to DNA strand breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes ADP-ribose onto nuclear acceptor proteins, such as histones and transcription factors.
The “classical” 113 kDa type I PARP is the major contributor of the poly(ADP-ribosyl)ating activity in higher eukaryotes. Type II PARP is smaller than the classical zinc-finger-containing PARP and is believed to participate in DNA repair during apoptosis. Type III PARP is a large protein containing ankyrin repeats and a PARP catalytic domain.
PARP consists of three domains: a DNA-binding domain (DBD), an automodification domain, and a catalytic domain. The DBD, a 42 kDa N-terminal region, extends from the initiator Met to Thr373 in human PARP. It contains two zinc fingers and two helix-turn-helix motifs and is rich in basic residues, which are involved in the interaction of the enzyme with DNA. The automodification domain located in the central region, resides between Ala374 and Leu525 in human PARP. A BRCT (BRCA1 C-terminus) domain that lies between Ala384 and Ser479 and consists of about 95 amino acids is found in several proteins that regulate cell-cycle checkpoints and DNA repair. BRCT domains are protein-protein interaction modules that allow BRCT-motif-containing proteins to establish strong and specific associations. The C-terminal catalytic domain, a 55 kDa segment, spans residues Thr526 to Trp1014 in human PARP. The catalytic activity of this fragment is not stimulated by DNA strand breaks. It corresponds only to the basal activity of the native enzyme. The ADPr transferase activity has been confined to a 40 kDa region at the extreme C-terminus of the enzyme, which is referred to as the minimal catalytic domain. This region can catalyze the initiation, elongation, and branching of ADPr polymers independently of the presence of DNA. The deletion of the last 45 amino acids at the C-terminal end of this domain completely abolishes enzyme activity. Residues spanning positions Leu859 to Tyr908 in human PARP are well conserved and comprise the “PARP signature” sequence.
The extent of poly(ADP-ribosyl)ation is an important determinant of NAD+ levels in cells. In normal, undamaged cells, NAD+ levels range from 400 to 500 mM. However, PARP activation following DNA damage by radiation or cytotoxic agents reduces NAD+ levels to about 100 mM within about 15 minutes. It is believed that during its automodification PARP becomes more charged, since each residue of ADPr adds two negative charges on to the molecule. This establishes an electro-repulsive gradient between the polymers of ADPr which are covalently linked to the enzyme and DNA. When the charge becomes too negative, the reaction reaches a “point of repulsion” and the interaction between PARP and DNA is lost. The poly(ADP-ribosyl)ated PARP molecule is consequently freed from the DNA strand break and its catalytic activity is abolished. Subsequently, poly(ADP-ribose) glycohydrolase (PARG) hydrolyses the polymers present on PARP, thereby allowing it to resume a new cycle of automodification in response to DNA damage. The presence of PARG during PARP automodification restores both its affinity for DNA and its catalytic activity.
DNA damage, the single most important factor in the regulation of pADPr reactions, can stimulate the catalytic activity of PARP by about 500-fold. Inhibition of PARP is shown to reduce DNA repair, increase the cytotoxicity of DNA-damaging agents, and enhance apoptosis. The cytotoxicity of PARP inhibitors is due to an increase in the half-life of DNA strand break, which increases genomic instability. PARP cleavage by caspase-3 is considered as an early event in apoptotic cell death. PARP degradation has also been reported during necrosis, although believed to be through a different process.
| | | | | | Inhibitors: Poly(ADP-ribose) Polymerase (PARP) and Poly(ADP-ribose) Glycohydrolase (PARG) |
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| ADP-HPD, Dihydrate, Ammonium Salt |
118415 |
| PARP Inhibitor I, 3-ABA |
165350 |
| PARP Inhibitor II, INH2BP |
407850 |
| PARP Inhibitor III, DPQ |
300270 |
| PARP Inhibitor IV, IQD |
419800 |
| PARP Inhibitor V, 4-ANI |
164585 |
| PARP Inhibitor VI, NU1025 |
493800 |
| PARP Inhibitor VIII, PJ34 |
528150 |
| PARP Inhibitor XI, DR2313 |
528819 |
| PARP Inhibitor IX, EB-47 |
324473 |
| PARP Inhibitor X, TIQ-A |
612100 |
| PARP Inhibitor XII |
528822 |
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| | | | Other Related Products | Product | | Comments | | PARP Inhibitor Set | 528820 | Provided as a 5 vial set. Each set contains 100 mg of 3-Aminobenzamide (Cat. No. 165350) and 5 mg each of 5-Iodo-6-amino- 1,2-benzopyrone (Cat. No. 407850), 1,5-Isoquinolinediol (Cat. No. 419800), and NU 1025 (Cat. No. 493800), and 1 mg of DPQ (Cat. No. 300270). | | PARP Cleavage Detection Kit | 512729 | Each kit is provided with a highly specific rabbit polyclonal antibody that detects 116 kDa PARP and the 85 kDa apoptosis-related cleavage fragment from human, bovine, rat, and mouse. |
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