PARP1

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Poly (ADP-ribose) polymerase 1
Protein PARP1 PDB 1uk0.png
PDB rendering based on 1uk0.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols PARP1 ; ADPRT; ADPRT 1; ADPRT1; ARTD1; PARP; PARP-1; PPOL; pADPRT-1
External IDs OMIM173870 MGI1340806 HomoloGene1222 ChEMBL: 3105 GeneCards: PARP1 Gene
EC number 2.4.2.30
RNA expression pattern
PBB GE PARP1 208644 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 142 11545
Ensembl ENSG00000143799 ENSMUSG00000026496
UniProt P09874 P11103
RefSeq (mRNA) NM_001618 NM_007415
RefSeq (protein) NP_001609 NP_031441
Location (UCSC) Chr 1:
226.55 – 226.6 Mb
Chr 1:
180.57 – 180.6 Mb
PubMed search [1] [2]

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene.[1]

Function[edit]

PARP1 works:

  • By modifying nuclear proteins by poly ADP-ribosylation.
  • In conjunction with BRCA, which acts on double strands; members of the PARP family act on single strands; or, when BRCA fails, PARP takes over those jobs as well.

PARP1 is involved in:

PARP1 is activated by:

Role in DNA damage repair[edit]

PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with siRNA or inhibiting PARP1 activity with small molecules reduces repair of ssDNA breaks. In the absence of PARP1, when these breaks are encountered during DNA replication, the replication fork stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via homologous recombination (HR) repair, a potentially error-free repair mechanism. For this reason, cells lacking PARP1 show a hyper-recombinagenic phenotype (e.g., an increased frequency of HR),[4][5][6] which has also been observed in vivo in mice using the pun assay.[7] Thus, if the HR pathway is functioning, PARP1 null mutants (cells without functioning PARP1) do not show an unhealthy phenotype, and in fact, PARP1 knockout mice show no negative phenotype and no increased incidence of tumor formation.[8]

Interaction with BRCA1 and BRCA2[edit]

However, both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. Therefore, cells that are deficient in BRCA1 or BRCA2 have been shown to be highly sensitive to PARP1 inhibition or knock-down, resulting in cell death by apoptosis, in stark contrast to cells with at least one good copy of both BRCA1 and BRCA2. Many breast cancers have defects in the BRCA1/BRCA2 HR repair pathway due to mutations in either BRCA1 or BRCA2, or other essential genes in the pathway (the latter termed cancers with "BRCAness"). Tumors with BRCAness are hypothesized to be highly sensitive to PARP1 inhibitors, and it has been demonstrated in mice that these inhibitors can both prevent BRCA1/2-deficient xenografts from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.

Application to cancer therapy[edit]

It is hypothesized that PARP1 inhibitors may prove highly effective therapies for cancers with BRCAness, due to the high sensitivity of the tumors to the inhibitor and the lack of deleterious effects on the remaining healthy cells with functioning BRCA HR pathway. This is in contrast to conventional chemotherapies, which are highly toxic to all cells and can induce DNA damage in healthy cells, leading to secondary cancer generation.[9][10]

Aging[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.[11] 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.[12] The Wrn protein is deficient in persons with Werner syndrome, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks.[13] These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore these observations suggest that PARP repair activity contributes to mammalian longevity, consistent with the DNA damage theory of aging.[14]

Interactions[edit]

PARP1 has been shown to interact with:

See also[edit]

References[edit]

  1. ^ Ha HC, Snyder SH (Oct 2000). "Poly(ADP-ribose) polymerase-1 in the nervous system". Neurobiol Dis 7 (4): 225–39. doi:10.1006/nbdi.2000.0324. PMID 10964595. 
  2. ^ "Entrez Gene: PARP1 poly (ADP-ribose) polymerase family, member 1". 
  3. ^ Nossa CW, Jain P, Tamilselvam B, Gupta VR, Chen LF, Schreiber V, Desnoyers S, Blanke SR (November 2009). "Activation of the abundant nuclear factor poly(ADP-ribose) polymerase-1 by Helicobacter pylori". Proc. Natl. Acad. Sci. U.S.A. 106 (47): 19998–20003. doi:10.1073/pnas.0906753106. PMC 2785281. PMID 19897724. Lay summaryphysorg.com. 
  4. ^ Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, Favaudon V (August 2008). "PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility". Nucleic Acids Res. 36 (13): 4454–64. doi:10.1093/nar/gkn403. PMC 2490739. PMID 18603595. 
  5. ^ Schultz N, Lopez E, Saleh-Gohari N, Helleday T (September 2003). "Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination". Nucleic Acids Res. 31 (17): 4959–64. doi:10.1093/nar/gkg703. PMC 212803. PMID 12930944. 
  6. ^ Waldman AS, Waldman BC (November 1991). "Stimulation of intrachromosomal homologous recombination in mammalian cells by an inhibitor of poly(ADP-ribosylation)". Nucleic Acids Res. 19 (21): 5943–7. doi:10.1093/nar/19.21.5943. PMC 329051. PMID 1945881. 
  7. ^ Claybon A, Karia B, Bruce C, Bishop AJ (July 2010). "PARP1 suppresses homologous recombination events in mice in vivo". Nucleic Acids Res 38 (21): 7538–45. doi:10.1093/nar/gkq624. PMC 2995050. PMID 20660013. 
  8. ^ Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF (March 1995). "Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease". Genes Dev. 9 (5): 509–20. doi:10.1101/gad.9.5.509. PMID 7698643. 
  9. ^ Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (April 2005). "Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase". Nature 434 (7035): 913–7. Bibcode:2005Natur.434..913B. doi:10.1038/nature03443. PMID 15829966. 
  10. ^ Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A (April 2005). "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy". Nature 434 (7035): 917–21. Bibcode:2005Natur.434..917F. doi:10.1038/nature03445. PMID 15829967. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ Lebel M, Lavoie J, Gaudreault I, Bronsard M, Drouin R (May 2003). "Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice". Am. J. Pathol. 162 (5): 1559–69. doi:10.1016/S0002-9440(10)64290-3. PMC 1851180. PMID 12707040. 
  14. ^ 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. ISBN 978-1604565812. 
  15. ^ a b c Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF (May 2004). "Aprataxin, a novel protein that protects against genotoxic stress". Hum. Mol. Genet. 13 (10): 1081–93. doi:10.1093/hmg/ddh122. PMID 15044383. 
  16. ^ Morgan HE, Jefferson LS, Wolpert EB, Rannels DE (April 1971). "Regulation of protein synthesis in heart muscle. II. Effect of amino acid levels and insulin on ribosomal aggregation". J. Biol. Chem. 246 (7): 2163–70. PMID 5555565. 
  17. ^ Cervellera MN, Sala A (April 2000). "Poly(ADP-ribose) polymerase is a B-MYB coactivator". J. Biol. Chem. 275 (14): 10692–6. doi:10.1074/jbc.275.14.10692. PMID 10744766. 
  18. ^ Hassa PO, Covic M, Hasan S, Imhof R, Hottiger MO (December 2001). "The enzymatic and DNA binding activity of PARP-1 are not required for NF-kappa B coactivator function". J. Biol. Chem. 276 (49): 45588–97. doi:10.1074/jbc.M106528200. PMID 11590148. 
  19. ^ Malanga M, Pleschke JM, Kleczkowska HE, Althaus FR (May 1998). "Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions". J. Biol. Chem. 273 (19): 11839–43. doi:10.1074/jbc.273.19.11839. PMID 9565608. 
  20. ^ a b Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Ménissier-de Murcia J (April 1998). "Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication". Nucleic Acids Res. 26 (8): 1891–8. doi:10.1093/nar/26.8.1891. PMC 147507. PMID 9518481. 
  21. ^ Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G (June 1998). "XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage". Mol. Cell. Biol. 18 (6): 3563–71. PMC 108937. PMID 9584196. 
  22. ^ Ku MC, Stewart S, Hata A (November 2003). "Poly(ADP-ribose) polymerase 1 interacts with OAZ and regulates BMP-target genes". Biochem. Biophys. Res. Commun. 311 (3): 702–7. doi:10.1016/j.bbrc.2003.10.053. PMID 14623329.