PARP1

From Wikipedia, the free encyclopedia

Poly (ADP-ribose) polymerase family, member 1

PDB rendering based on 1uk0.

Available structures: 1uk0, 1uk1, 1wok, 2cok, 2cr9, 2cs2, 2dmj

Identifiers

Symbol(s)

PARP1; ADPRT; ADPRT1; PARP; PARP-1; PPOL; pADPRT-1

External IDs

OMIM: 173870 MGI: 1340806 HomoloGene: 1222

Gene ontology
Molecular Function:	• DNA binding • NAD+ ADP-ribosyltransferase activity • zinc ion binding • transferase activity, transferring glycosyl groups • identical protein binding • metal ion binding • NAD binding
Cellular Component:	• intracellular • nucleus • nuclear envelope • nucleolus
Biological Process:	• telomere maintenance • base-excision repair • transcription from RNA polymerase II promoter • protein amino acid ADP-ribosylation • regulation of growth rate

RNA expression pattern

More reference expression data

Orthologs

Human

Mouse

n/a

n/a

Refseq

NM_001618 (mRNA)
NP_001609 (protein)

NM_007415 (mRNA)
NP_031441 (protein)

Location

Chr 1: 224.62 - 224.66 Mb

n/a

Pubmed search

[1]

[2]

Poly (ADP-ribose) polymerase family, member 1, also known as PARP1, is a human gene.

This gene encodes a chromatin-associated enzyme, poly-ADP ribose polymerase-1, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery of cell from DNA damage. In addition, this enzyme may be the site of mutation in Fanconi anemia, and may participate in the pathophysiology of type I diabetes.^[1]

1 Role in DNA damage repair, interaction with BRCA1 and BRCA2, and cancer therapy
2 See also
3 References
4 Further reading

[edit] Role in DNA damage repair, interaction with BRCA1 and BRCA2, and cancer therapy

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 abscence 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, an error-free repair mechanism. 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.

However, both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. Therefore, cells which 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 — either due to mutations in 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 as well as eradicate tumors having previously formed from BRCA1/2-deficient xenografts. 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.^[2]^[3]

[edit] See also

Poly ADP ribose polymerase

[edit] References

^ Entrez Gene: PARP1 poly (ADP-ribose) polymerase family, member 1.
^ Bryant, Helen E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.; Helleday, T. (2005). "Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase". Nature 434: 913–917. doi:10.1038/nature03443. PMID 15829966.
^ Farmer, Hannah; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D A.; Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C.; Martin, M. M. B.; Jackson, S. P.; Smith, G. C. M.; Ashworth, A. (2005). "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy". Nature 434: 917–921. doi:10.1038/nature03445. PMID 15829967.

[edit] Further reading

Helleday T, Bryant HE, Schultz N (2006). "Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy.". Cell Cycle 4 (9): 1176–8. PMID 16123586.
Baumgartner M, Schneider R, Auer B, et al. (1992). "Fluorescence in situ mapping of the human nuclear NAD+ ADP-ribosyltransferase gene (ADPRT) and two secondary sites to human chromosomal bands 1q42, 13q34, and 14q24.". Cytogenet. Cell Genet. 61 (3): 172–4. PMID 1424803.
Schreiber V, Molinete M, Boeuf H, et al. (1992). "The human poly(ADP-ribose) polymerase nuclear localization signal is a bipartite element functionally separate from DNA binding and catalytic activity.". EMBO J. 11 (9): 3263–9. PMID 1505517.
Ogura T, Nyunoya H, Takahashi-Masutani M, et al. (1990). "Characterization of a putative promoter region of the human poly(ADP-ribose) polymerase gene: structural similarity to that of the DNA polymerase beta gene.". Biochem. Biophys. Res. Commun. 167 (2): 701–10. PMID 2108670.
Gradwohl G, Ménissier de Murcia JM, Molinete M, et al. (1990). "The second zinc-finger domain of poly(ADP-ribose) polymerase determines specificity for single-stranded breaks in DNA.". Proc. Natl. Acad. Sci. U.S.A. 87 (8): 2990–4. PMID 2109322.
Simonin F, Ménissier-de Murcia J, Poch O, et al. (1990). "Expression and site-directed mutagenesis of the catalytic domain of human poly(ADP-ribose)polymerase in Escherichia coli. Lysine 893 is critical for activity.". J. Biol. Chem. 265 (31): 19249–56. PMID 2121735.
Ikejima M, Noguchi S, Yamashita R, et al. (1991). "The zinc fingers of human poly(ADP-ribose) polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other structures recognize intact DNA.". J. Biol. Chem. 265 (35): 21907–13. PMID 2123876.
Yokoyama Y, Kawamoto T, Mitsuuchi Y, et al. (1991). "Human poly(ADP-ribose) polymerase gene. Cloning of the promoter region.". Eur. J. Biochem. 194 (2): 521–6. PMID 2125269.
Ushiro H, Yokoyama Y, Shizuta Y (1987). "Purification and characterization of poly (ADP-ribose) synthetase from human placenta.". J. Biol. Chem. 262 (5): 2352–7. PMID 2434482.
Herzog H, Zabel BU, Schneider R, et al. (1989). "Human nuclear NAD+ ADP-ribosyltransferase: localization of the gene on chromosome 1q41-q42 and expression of an active human enzyme in Escherichia coli.". Proc. Natl. Acad. Sci. U.S.A. 86 (10): 3514–8. PMID 2498872.
Auer B, Nagl U, Herzog H, et al. (1990). "Human nuclear NAD+ ADP-ribosyltransferase(polymerizing): organization of the gene.". DNA 8 (8): 575–80. PMID 2513174.
Kurosaki T, Ushiro H, Mitsuuchi Y, et al. (1987). "Primary structure of human poly(ADP-ribose) synthetase as deduced from cDNA sequence.". J. Biol. Chem. 262 (33): 15990–7. PMID 2824474.
Cherney BW, McBride OW, Chen DF, et al. (1988). "cDNA sequence, protein structure, and chromosomal location of the human gene for poly(ADP-ribose) polymerase.". Proc. Natl. Acad. Sci. U.S.A. 84 (23): 8370–4. PMID 2891139.
Alkhatib HM, Chen DF, Cherney B, et al. (1987). "Cloning and expression of cDNA for human poly(ADP-ribose) polymerase.". Proc. Natl. Acad. Sci. U.S.A. 84 (5): 1224–8. PMID 3029772.
Loetscher P, Alvarez-Gonzalez R, Althaus FR (1987). "Poly(ADP-ribose) may signal changing metabolic conditions to the chromatin of mammalian cells.". Proc. Natl. Acad. Sci. U.S.A. 84 (5): 1286–9. PMID 3103132.
Suzuki H, Uchida K, Shima H, et al. (1987). "Molecular cloning of cDNA for human poly(ADP-ribose) polymerase and expression of its gene during HL-60 cell differentiation.". Biochem. Biophys. Res. Commun. 146 (2): 403–9. PMID 3113420.
Uchida K, Morita T, Sato T, et al. (1987). "Nucleotide sequence of a full-length cDNA for human fibroblast poly(ADP-ribose) polymerase.". Biochem. Biophys. Res. Commun. 148 (2): 617–22. PMID 3120710.
Schneider R, Auer B, Kühne C, et al. (1988). "Isolation of a cDNA clone for human NAD+: protein ADP-ribosyltransferase.". Eur. J. Cell Biol. 44 (2): 302–7. PMID 3121332.
Carter SG, Berger NA (1983). "Purification and characterization of human lymphoid poly(adenosine diphosphate ribose) polymerase.". Biochemistry 21 (22): 5475–81. PMID 6293541.
Gu Y, Sarnecki C, Aldape RA, et al. (1995). "Cleavage of poly(ADP-ribose) polymerase by interleukin-1 beta converting enzyme and its homologs TX and Nedd-2.". J. Biol. Chem. 270 (32): 18715–8. PMID 7642516.