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NAD+ ADP-ribosyltransferase or poly ADP-ribose polymerase
Function:
- NAD+ ADP-ribosyltransferase binds to DNA damage caused by ionizing radiation & alkylating agents & automodifies itself with NAD forming branched chain polymers of ADP ribose at several sites
- polymers are short-lived (1-2 min) because poly ADP-ribose polymerase always occurs together with poly ADP ribose glycohydrolase
- the overall process consumes NAD & produces nicotinamide, ADP-ribose & branched oligo-(ADP-ribose) molecules
- PARP deficient mutants are not deficient in DNA repair; however, PARP may serve a role in recognition of DNA damage, recruitment of the repair apparatus to the site of DNA damage & as a meter of the overall extent of genomic damage sustained
Expression:
- there are about 1 million molecules of PARP in mammalian nuclei
Compartment:
- the enzyme is conserved in most eukaryotes
- not expressed in yeast
Pharmacology:
- olaparib (Lynparza) is a poly ADP-ribose polymerase inhibitor FDA-approved to treat advanced ovarian cancer with germline BRCA mutations
- niraparib (Zejula) is a poly ADP-ribose polymerase inhibitor FDA-approved for maintenance treatment of recurrent epithelial cancers (ovarian cancer, fallopian tube cancer, primary peritoneal cancer)
- PARP inhibitors are FDA-approved to treat androgen-independent metastatic prostate cancer
Interactions
molecular events
Related
PARP inhibitor
poly(ADP-ribose)glycohydrolase (pARG)
Specific
poly [ADP-ribose] polymerase 10; PARP-10; ADP-ribosyltransferase diphtheria toxin-like 10; ARTD10 (PARP10)
poly [ADP-ribose] polymerase 11 (PARP-11, PARP11, C12orf6)
poly [ADP-ribose] polymerase 12; PARP-12; zinc finger CCCH domain-containing protein 1 (PARP12, ZC3HDC1)
poly [ADP-ribose] polymerase 14; PARP-14; ADP-ribosyltransferase diphtheria toxin-like 8; ARTD8; B aggressive lymphoma protein 2 (PARP14, BAL2, KIAA1268)
poly [ADP-ribose] polymerase 15; PARP-15; ADP-ribosyltransferase diphtheria toxin-like 7; ARTD7; B-aggressive lymphoma protein 3 (PARP15, BAL3)
poly [ADP-ribose] polymerase 16; ADP-ribosyltransferase diphtheria toxin-like 15; ARTD15; mono [ADP-ribose] polymerase PARP16; PARP-16 (PARP16, C15orf30)
poly [ADP-ribose] polymerase 1; PARP-1; NAD(+) ADP-ribosyltransferase 1; ADPRT 1; poly[ADP-ribose] synthase 1 (PARP1, ADPRT, PPOL)
poly [ADP-ribose] polymerase 2; PARP-2; hPARP-2; NAD(+) ADP-ribosyltransferase 2; ADPRT-2; poly[ADP-ribose] synthase 2; pADPRT-2 (PARP2 ADPRT2 ADPRTL2)
poly [ADP-ribose] polymerase 3; PARP-3; hPARP-3; IRT1; NAD+ ADP-ribosyltransferase 3; ADPRT-3; poly[ADP-ribose] synthase 3; pADPRT-3 (PARP3 ADPRT3 ADPRTL3)
poly [ADP-ribose] polymerase 4; PARP-4; 193 kD vault protein; PARP-related/IalphaI-related H5/proline-rich; PH5P; vault poly(ADP-ribose) polymerase; VPARP (PARP4, ADPRTL1, KIAA0177, PARPL)
poly [ADP-ribose] polymerase 6; PARP-6; ADP-ribosyltransferase diphtheria toxin-like 17; ARTD17 (PARP6)
poly [ADP-ribose] polymerase 7; ADP-ribosyltransferase diphtheria toxin-like 14; ARTD14; TCDD-inducible poly [ADP-ribose] polymerase; PARP-7 (TIPARP PARP7)
poly [ADP-ribose] polymerase 8; PARP-8; ADP-ribosyltransferase diphtheria toxin-like 16; ARTD16 (PARP8)
poly [ADP-ribose] polymerase 9; PARP-9; B aggressive lymphoma protein (PARP9, BAL)
General
ADP-ribosyltransferase
Figures/Diagrams
Mechanism of base excision repair (v.2)
Properties
SIZE: MW = 113 kD
entity length = 1013 aa
MOTIF: DNA-binding motif
SITE: 1-371
MOTIF: nuclear translocation signal {206-208} <1/2SITE>
nuclear translocation signal {220-225} <1/2SITE>
BRCA1 C-terminal (BRCT) motif
SITE: 384-460
automodification {372-523}
MOTIF: binding site (15)
SITE: 406-519
FOR-BINDING-OF: ADP ribose
cofactor-binding site [524-1013]
FOR-BINDING-OF: NAD
active site
SITE: 892
References
- UniProt :accession P09874
- Lindahl T et al
Post-translational modification of poly(ADP-ribose) polymerase
induced by DNA strand breaks.
TIBS 20:405 1995
PMID: 853315