World Library  
Flag as Inappropriate
Email this Article

Poly ADP ribose polymerase

Article Id: WHEBN0001959815
Reproduction Date:

Title: Poly ADP ribose polymerase  
Author: World Heritage Encyclopedia
Language: English
Subject: Pentosyltransferase, Olaparib, DNA repair, PARP, PARP inhibitor
Collection: Dna Repair, Ec 2.4.2, Programmed Cell Death
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Poly ADP ribose polymerase

NAD+ ADP-ribosyltransferase
Identifiers
EC number 2.4.2.30
CAS number 58319-92-9
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes involving mainly DNA repair and programmed cell death.

Contents

  • Members of PARP family 1
  • PARP structure 2
  • Functions 3
  • Activity 4
    • Role in repairing DNA nicks 4.1
    • PARP activity and lifespan 4.2
    • Role of tankyrases 4.3
    • Role in cell death 4.4
    • Role in epigenetic DNA modification 4.5
  • PARP Inactivation 5
  • See also 6
  • References 7
  • External links 8

Members of PARP family

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

  • PARP1, PARP2, VPARP (PARP4), Tankyrase-1 and -2 (PARP-5a or TNKS, and PARP-5b or TNKS2) have a confirmed PARP activity.

PARP structure

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.

Functions

PARP is found in the cell’s nucleus. The main role is to detect and signal single-strand DNA breaks (SSB) to the enzymatic machinery involved in the SSB repair. PARP activation is an immediate cellular response to metabolic, chemical, or radiation-induced DNA SSB damage. Once PARP detects a SSB, it binds to the DNA, and, after a structural change, begins the synthesis of a poly (ADP-ribose) chain (PAR) as a signal for the other DNA-repairing enzymes such as 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).[1]

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 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,[2] including expression of inflammatory genes:[3] PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF.[4]

Activity

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

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.[5]

PARP activity and lifespan

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.[6] The difference in longevity between the longest- (humans) and shortest-lived species tested (rat) was 5-fold. The automodification reaction of human and rat PARP-1 was analyzed and human PARP-1 was found to have a two-fold higher poly(ADP-ribosyl)ation capacity than the rat enzyme, which could account, in part, for the higher PARP activity in humans than rats.[7] 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,[8] 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.[9][10]

Role of tankyrases

The tankyrases are PARPs that comprise ankyrin repeats, 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 vesicle (GSVs) with insulin-responsive amino peptidase (IRAP). It also plays a role in spindle assembly through its interaction with nuclear mitotic apparatus (NuMa), therefore allowing bipolarity. In the absence of TNKs, mitosis arrest is observed in pre-anaphase through Mad2 kinetochore 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

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.[11] This mechanism appears to be caspase-independent. Cleavage of Parp, by enzymes such as caspases or cathepsins, typically inactivate 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

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 Inactivation

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.[12]

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.

See also

References

  1. ^ 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.  
  2. ^ 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.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ Bernstein C, Bernstein H (2004). "Aging and sex, DNA repair in". In Meyers RA. Encyclopedia of molecular cell biology and molecular medicine. Weinheim: Wiley-VCH Verlag. pp. 53–98.  
  10. ^ Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Kimura H, Suzuki A, ed. Cancer and aging as consequences of un-repaired DNA damage. New York: Nova Science Publishers, Inc. pp. 1–47.  
  11. ^ 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.  
  12. ^ 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.  

External links

  • Entry for a PARP immunoassay at bioreagents.com
  • PARP - Poly (ADP-ribose) polymerase at inotekcorp.com
  • The PARP Link Homepage at parplink.u-strasbg.fr
  • Poly ADP Ribose Polymerase at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Parp Inhibitors Information Site
  • PARP Activity and Inhibition Assays at trevigen.com
This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 



Copyright © World Library Foundation. All rights reserved. eBooks from Hawaii eBook Library are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.