Poly (ADP-ribose) polymerase

From Wikipedia, the free encyclopedia
  (Redirected from Poly ADP ribose polymerase)
Jump to navigation Jump to search
NAD+ ADP-ribosyltransferase
EC number2.4.2.30
CAS number58319-92-9
IntEnzIntEnz view
ExPASyNiceZyme view
MetaCycmetabolic pathway
PDB structuresRCSB PDB PDBe PDBsum

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.[1]

Members of PARP family[edit]

The PARP family comprises 17 members (10 putative).[citation needed] They have all very different structures and functions in the cell.


PARP is composed of four domains of interest: a DNA-binding domain, a caspase-cleaved domain (see below), an auto-modification domain, and a catalytic domain. The DNA-binding domain is composed of two zinc finger motifs. In the presence of damaged DNA (base pair-excised), the DNA-binding domain will bind the DNA and induce a conformational shift. It has been shown that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP. The auto-modification domain is responsible for releasing the protein from the DNA after catalysis. Also, it plays an integral role in cleavage-induced inactivation.


The main role of PARP (found in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair.

Once PARP detects a SSB, it binds to the DNA, undergoes a structural change, and begins the synthesis of a polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes. Target enzymes include DNA ligase III (LigIII), DNA polymerase beta (polβ), and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).[2]

NAD+ is required as substrate for generating ADP-ribose monomers. It has been thought that overactivation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion and necrotic cell death, since glucose oxidation is inhibited. But more recently it was suggested that inhibition of hexokinase activity leads to defects in glycolysis. Andrabi, PNAS 2014. Note below that PARP is inactivated by caspase-3 cleavage during programmed cell death.

PARP enzymes are essential in a number of cellular functions,[3] including expression of inflammatory genes:[4] PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF.[5]


The catalytic domain is responsible for Poly (ADP-ribose) polymerization. This domain has a highly conserved motif that is common to all members of the PARP family. PAR polymer can reach lengths of up to 200 nucleotides before inducing apoptotic processes. The formation of PAR polymer is similar to the formation of DNA polymer from nucleoside triphosphates. Normal DNA synthesis requires that a pyrophosphate act as the leaving group, leaving a single phosphate group linking deoxyribose sugars. PAR is synthesized using nicotinamide (NAM) as the leaving group. This leaves a pyrophosphate as the linking group between ribose sugars rather than single phosphate groups. This creates some special bulk to a PAR bridge, which may have an additional role in cell signaling.

Role in repairing DNA nicks[edit]

One important function of PARP is assisting in the repair of single-strand DNA nicks. It binds sites with single-strand breaks through its N-terminal zinc fingers and will recruit XRCC1, DNA ligase III, DNA polymerase beta, and a kinase to the nick. This is called base excision repair (BER). PARP-2 has been shown to oligomerize with PARP-1 and, therefore, is also implicated in BER. The oligomerization has also been shown to stimulate PARP catalytic activity. PARP-1 is also known for its role in transcription through remodeling of chromatin by PARylating histones and relaxing chromatin structure, thus allowing transcription complex to access genes.

PARP-1 and PARP-2 are activated by DNA single-strand breaks, and both PARP-1 and PARP-2 knockout mice have severe deficiencies in DNA repair, and increased sensitivity to alkylating agents or ionizing radiation.[6]

PARP activity and lifespan[edit]

PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear leukocyte blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla, elephant and man) correlates with maximum lifespan of the species.[7] The difference in activity between the longest- (humans) and shortest-lived species tested (rat) was 5-fold. Although the enzyme kinetics (unimolecular rate constant (kcat), Km and kcat/km) of the two enzymes were not significantly different human PARP-1 was found to have a two-fold higher specific automodification capacity than the rat enzyme, which the authors posited could account, in part, for the higher PARP activity in humans than rats.[8] Lymphoblastoid cell lines established from blood samples of humans who were centenarians (100 years old or older) have significantly higher PARP activity than cell lines from younger (20 to 70 years old) individuals,[9] again indicating a linkage between longevity and repair capability.

These findings suggest that PARP-mediated DNA repair capability contributes to mammalian longevity. Thus these findings lend support to the DNA damage theory of aging which assumes that un-repaired DNA damage is the underlying cause of aging and that DNA repair capability contributes to longevity.[10][11]

Role of tankyrases[edit]

The tankyrases (TNKs) are PARPs that comprise ankyrin repeats, an oligomerization domain (SAM), and a PARP catalytic domain (PCD). Tankyrases are also known as PARP-5a and PARP-5b. They were named for their interaction with the telomere-associated TRF1 proteins and ankyrin repeats. They may allow the removal of telomerase-inhibiting complexes from chromosome ends to allow for telomere maintenance. Through their SAM domain and ANKs, they can oligomerize and interact with many other proteins, such as TRF1, TAB182 (TNKS1BP1), GRB14, IRAP, NuMa, EBNA-1, and Mcl-1. They have multiple roles in the cell, vesicular trafficking through its interaction in GLUT4 vesicles with insulin-responsive aminopeptidase (IRAP). It also plays a role in mitotic spindle assembly through its interaction with nuclear mitotic apparatus protein 1 (NuMa), therefore allowing the necessary bipolar orientation. In the absence of TNKs, mitosis arrest is observed in pre-anaphase through Mad2 spindle checkpoint. TNKs can also PARsylate Mcl-1L and Mcl-1S and inhibit both their pro- and anti-apoptotic function. Relevance of this is not yet known.

Role in cell death[edit]

PARP can be activated in cells experiencing stress and/or DNA damage. Activated PARP can deplete the ATP of a cell in an attempt to repair the damaged DNA. ATP depletion in a cell leads to lysis and cell death (necrosis). PARP also has the ability to induce programmed cell death, via the production of PAR, which stimulates mitochondria to release AIF.[12] This mechanism appears to be caspase-independent. Cleavage of Parp, by enzymes such as caspases or cathepsins, typically inactivates Parp. The size of the cleavage fragments can give insight into which enzyme was responsible for the cleavage, and can be useful in determining which cell death pathway has been activated.

Role in epigenetic DNA modification[edit]

PARP-mediated post-translational modification of proteins such as CTCF can affect the amount of DNA methylation at CpG dinucleotides. This regulates the insulator features of CTCF can differentially mark the copy of DNA inherited from either the maternal or the paternal DNA through the process known as genomic imprinting. PARP has also been proposed to affect the amount of DNA methylation by directly binding to the DNA methyltransferase DNMT-1 after attaching poly ADP-ribose chains to itself after interaction with CTCF and affecting DNMT1's enzymatic activity.


PARP is inactivated by caspase cleavage. It is believed that normal inactivation occurs in systems where DNA damage is extensive. In these cases, more energy would be invested in repairing damage than is feasible, so that energy is instead retrieved for other cells in the tissue through programmed cell death. Besides degradation, there is recent evidence about reversible downregulation mechanisms for PARP, among these an "autoregulatory loop", which is driven by PARP1 itself and modulated by the YY1 transcription factor.[13]

While in vitro cleavage by caspase occurs throughout the caspase family, preliminary data suggest that caspase-3 and caspase-7 are responsible for in vivo cleavage. Cleavage occurs at aspartic acid 214 and glycine 215, separating PARP into a 24kDA and 89kDA segment. The smaller moiety includes the zinc finger motif requisite in DNA binding. The 89 kDa fragment includes the auto-modification domain and catalytic domain. The putative mechanism of PCD activation via PARP inactivation relies on the separation of the DNA-binding region and the auto-modification domain. The DNA-binding region is capable of doing so independent of the rest of the protein, cleaved or not. It is unable, however, to dissociate without the auto-modification domain. In this way, the DNA-binding domain will attach to a damaged site and be unable to effect repair, as it no longer has the catalytic domain. The DNA-binding domain prevents other, non-cleaved PARP from accessing the damaged site and initiating repairs. This model suggests that this "sugar plug" can also begin the signal for apoptosis.

Plant PARPs[edit]

Roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied.[14][15] Plants have a PARP1 with substantial similarity to animal PARP1 but intriguingly, in Arabidopsis thaliana and presumably other plants, PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.[16] The plant PARP2 carries PARP regulatory and catalytic domains with only intermediate similarity to PARP1, and carries N-terminal SAP DNA binding motifs rather than the Zn-finger DNA binding motifs of plant and animal PARP1 proteins.[16]

See also[edit]


  1. ^ Herceg Z, Wang ZQ (2001). "Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death". Mutat Res. 422 (1–2): 97–110. PMID 11376691.
  2. ^ Isabelle M, Moreel X, Gagné JP, Rouleau M, Ethier C, Gagné P, Hendzel MJ, Poirier GG (2010). "Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry". Proteome Sci. 8: 22. doi:10.1186/1477-5956-8-22. PMC 2861645. PMID 20388209.
  3. ^ Piskunova TS, Yurova MN, Ovsyannikov AI, Semenchenko AV, Zabezhinski MA, Popovich IG, Wang ZQ, Anisimov VN (2008). "Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice". Curr Gerontol Geriatr Res: 754190. doi:10.1155/2008/754190. PMC 2672038. PMID 19415146.
  4. ^ Espinoza LA, Smulson ME, Chen Z (May 2007). "Prolonged poly(ADP-ribose) polymerase-1 activity regulates JP-8-induced sustained cytokine expression in alveolar macrophages". Free Radic. Biol. Med. 42 (9): 1430–40. doi:10.1016/j.freeradbiomed.2007.01.043. PMID 17395016.
  5. ^ Zerfaoui M, Suzuki Y, Naura AS, Hans CP, Nichols C, Boulares AH (January 2008). "Nuclear translocation of p65 NF-kappaB is sufficient for VCAM-1, but not ICAM-1, expression in TNF-stimulated smooth muscle cells: Differential requirement for PARP-1 expression and interaction". Cell. Signal. 20 (1): 186–94. doi:10.1016/j.cellsig.2007.10.007. PMC 2278030. PMID 17993261.
  6. ^ Bürkle A, Brabeck C, Diefenbach J, Beneke S (May 2005). "The emerging role of poly(ADP-ribose) polymerase-1 in longevity". Int. J. Biochem. Cell Biol. 37 (5): 1043–53. doi:10.1016/j.biocel.2004.10.006. PMID 15743677.
  7. ^ Grube K, Bürkle A (December 1992). "Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span". Proc. Natl. Acad. Sci. U.S.A. 89 (24): 11759–63. Bibcode:1992PNAS...8911759G. doi:10.1073/pnas.89.24.11759. PMC 50636. PMID 1465394.
  8. ^ Beneke S, Alvarez-Gonzalez R, Bürkle A (October 2000). "Comparative characterisation of poly(ADP-ribose) polymerase-1 from two mammalian species with different life span". Exp. Gerontol. 35 (8): 989–1002. doi:10.1016/s0531-5565(00)00134-0. PMID 11121685.
  9. ^ Muiras ML, Müller M, Schächter F, Bürkle A (April 1998). "Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians". J. Mol. Med. 76 (5): 346–54. doi:10.1007/s001090050226. PMID 9587069.
  10. ^ Bernstein C, Bernstein H (2004). "Aging and sex, DNA repair in". In Meyers RA (ed.). Encyclopedia of molecular cell biology and molecular medicine. Weinheim: Wiley-VCH Verlag. pp. 53–98. doi:10.1002/3527600906.mcb.200200009. ISBN 3-527-30542-4.
  11. ^ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Kimura H, Suzuki A (eds.). Cancer and aging as consequences of un-repaired DNA damage. New York: Nova Science Publishers, Inc. pp. 1–47. ISBN 978-1604565812.
  12. ^ Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL (November 2006). "Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death". Proc. Natl. Acad. Sci. U.S.A. 103 (48): 18314–9. Bibcode:2006PNAS..10318314Y. doi:10.1073/pnas.0606528103. PMC 1838748. PMID 17116881.
  13. ^ Doetsch M, Gluch A, Poznanović G, Bode J, Vidaković M (2012). "YY1-binding sites provide central switch functions in the PARP-1 gene expression network". PLOS ONE. 7 (8): e44125. Bibcode:2012PLoSO...744125D. doi:10.1371/journal.pone.0044125. PMC 3429435. PMID 22937159.
  14. ^ Briggs AG, Bent AF (July 2011). "Poly(ADP-ribosyl)ation in plants". Trends in Plant Science. 16 (7): 372–80. doi:10.1016/j.tplants.2011.03.008. PMID 21482174.
  15. ^ Feng B, Liu C, Shan L, He P (December 2016). "Protein ADP-Ribosylation Takes Control in Plant-Bacterium Interactions". PLoS Pathogens. 12 (12): e1005941. doi:10.1371/journal.ppat.1005941. PMC 5131896. PMID 27907213.
  16. ^ a b Song J, Keppler BD, Wise RR, Bent AF (May 2015). "PARP2 Is the Predominant Poly(ADP-Ribose) Polymerase in Arabidopsis DNA Damage and Immune Responses". PLoS Genetics. 11 (5): e1005200. doi:10.1371/journal.pgen.1005200. PMC 4423837. PMID 25950582.

External links[edit]