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{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}
'''Poly [ADP-ribose] polymerase 1''' ('''PARP-1''') also known as '''NAD<sup>+</sup> ADP-ribosyltransferase 1''' or '''poly[ADP-ribose] synthase 1''' is an [[enzyme]] that in humans is encoded by the ''PARP1'' [[gene]].<ref name="pmid10964595">{{cite journal | vauthors = Ha HC, Snyder SH | title = Poly(ADP-ribose) polymerase-1 in the nervous system | journal = [[Neurobiology of Disease]] | volume = 7 | issue = 4 | pages = 225–39 | date =
== Function ==
PARP1 works:
* By using [[Nicotinamide adenine dinucleotide|NAD+]] to synthesize poly [[Adenosine diphosphate ribose|ADP ribose]] (PAR) and transferring PAR [[Moiety (chemistry)|moieties]] to proteins ([[ADP-ribosylation]]).<ref>{{cite journal | pmid = 32079521 | year = 2020 | last1 = Nilov | first1 = DK | last2 = Pushkarev | first2 = SV | last3 = Gushchina | first3 = IV | last4 = Manasaryan | first4 = GA | last5 = Kirsanov | first5 = KI | last6 = Švedas | first6 = VK | title = Modeling of the enzyme-substrate complexes of human poly(ADP-ribose) polymerase 1 | volume = 85 | pages = 99–107 | journal = Biochemistry (Moscow) | issue = 1 | doi=10.1134/S0006297920010095| s2cid = 211028760 }}</ref>
* In conjunction with BRCA, which acts on double strands; members of the [[Poly ADP ribose polymerase|PARP]] family act on single strands; or, when BRCA fails, PARP takes over those jobs as well (in a DNA repair context).
PARP1 is involved in:
* Differentiation, proliferation, and tumor transformation
* Normal or abnormal recovery from DNA damage
*
* Induction of inflammation.<ref name="pmid23050038">{{cite journal | vauthors=Mangerich A, Bürkle A | title=Pleiotropic cellular functions of PARP1 in longevity and aging: genome maintenance meets inflammation | journal=[[Oxidative Medicine and Cellular Longevity]] | volume=2012 | pages=321653 | year=2012 | doi = 10.1155/2012/321653 | pmc=3459245 | pmid=23050038| doi-access=free }}</ref>
* The pathophysiology of [[type I diabetes]].<ref name="entrez">{{cite web | title = Entrez Gene: PARP1 poly (ADP-ribose) polymerase family, member 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=142
PARP1 is activated by:
* [[Helicobacter pylori]] in the development and proliferation of [[gastric cancer]].<ref name="pmid19897724">{{cite journal | vauthors = Nossa CW, Jain P, Tamilselvam B, Gupta VR, Chen LF, Schreiber V, Desnoyers S, Blanke SR | display-authors = 6 | title = Activation of the abundant nuclear factor poly(ADP-ribose) polymerase-1 by Helicobacter pylori | journal = [[Proceedings of the National Academy of Sciences of the United States of America]] | volume = 106 | issue = 47 | pages = 19998–20003 | date =
*{{cite web |date=January 6, 2010 |title=Team finds link between stomach-cancer bug and cancer-promoting factor |website=Medical Xpress |url=http://www.physorg.com/news182001373.html}}</ref>
=== Role in DNA damage repair ===
PARP1 acts as a first responder that detects [[DNA damage (naturally occurring)|DNA damage]] and then facilitates choice of [[DNA repair|repair]] pathway.<ref name="Pascal2018">{{cite journal | vauthors = Pascal JM | title = The comings and goings of PARP-1 in response to DNA damage | journal = [[DNA Repair (journal)|DNA Repair]] | volume = 71 | pages = 177–182 | date = November 2018 | pmid = 30177435 | pmc = 6637744 | doi = 10.1016/j.dnarep.2018.08.022 }}</ref> PARP1 contributes to repair efficiency by [[ADP-ribosylation]] of [[histone]]s leading to decompaction of [[chromatin]] structure, and by interacting with and modifying multiple [[DNA repair]] factors.<ref name="pmid33028824" /> PARP1 is implicated in the regulation of several DNA repair processes including the pathways of [[nucleotide excision repair]], [[non-homologous end joining]], [[microhomology-mediated end joining]], [[homologous recombination]]al repair, and [[DNA mismatch repair]].<ref name=Pascal2018/>
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),<ref name="pmid18603595">{{cite journal | vauthors = Godon C, Cordelières FP, Biard D, Giocanti N, Mégnin-Chanet F, Hall J, Favaudon V | title = PARP inhibition versus PARP-1 silencing: different outcomes in terms of single-strand break repair and radiation susceptibility | journal = [[Nucleic Acids Research]] | volume = 36 | issue = 13 | pages = 4454–64 | date = === Role in inflammation ===
PARP1 is required for [[NF-κB]] [[Transcription (biology)|transcription]] of [[Inflammation|proinflammatory]] mediators such as [[tumor necrosis factor]], [[interleukin 6]], and inducible [[nitric oxide synthase]].<ref name="pmid23050038" /><ref name="pmid28974953">{{cite journal | vauthors=Sethi GS, Dharwal V, Naura AS | title=Poly(ADP-Ribose)Polymerase-1 in Lung Inflammatory Disorders: A Review | journal=[[Frontiers in Immunology]] | volume=8 | pages=1172 | year=2017 | doi = 10.3389/fimmu.2017.01172 | pmc=5610677 | pmid=28974953| doi-access=free }}</ref> PARP1 activity contributes to the proinflammatory [[macrophage]]s that increase with age in many tissues.<ref name="pmid32774895">{{cite journal | vauthors=Yarbro JR, Emmons RS, Pence BD | title=Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD | journal=[[Immunometabolism (journal)|Immunometabolism]] | volume=2 | issue=3 | pages=e200026 | year=2020 | doi = 10.20900/immunometab20200026 | pmc=7409778 | pmid=32774895}}</ref> ADP-riboyslation of the [[HMGB1]] [[high-mobility group]] protein by PARP1 inhibits removal of [[apoptosis|apoptotic]] cells, thereby sustaining inflammation.<ref name="pmid31877876">{{cite journal | vauthors=Pazzaglia S, Pioli C | title=Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases | journal=[[Cell (journal)|Cells]] | volume=9 | issue=1 | pages=41 | year=2019 | doi = 10.3390/cells9010041 | pmc=7017201 | pmid=31877876| doi-access=free }}</ref>
In [[asthma]] PARP1 facilitates recruitment and function of immune cells, including [[T helper cell|CD4+ T-cells]], [[eosinophil]]s, and [[dendritic cell]]s.<ref name="pmid28974953" />
===Over-expression in cancer===
PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway [[microhomology-mediated end joining]] (MMEJ).<ref name="pmid25789972">{{cite journal | vauthors = Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC | title = Homology and enzymatic requirements of microhomology-dependent alternative end joining | journal = [[Cell Death
PARP1 is also over-expressed when its promoter region [[ETS1|ETS]] site is [[epigenetics|epigenetically]] hypomethylated, and this contributes to progression to endometrial cancer,<ref name="pmid23762867">{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Hypomethylation of ETS transcription factor binding sites and upregulation of PARP1 expression in endometrial cancer | journal =
PARP1 is also over-expressed in a number of other cancers, including neuroblastoma,<ref name="pmid25563294">{{cite journal | vauthors = Newman EA, Lu F, Bashllari D, Wang L, Opipari AW, Castle VP | title = Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma | journal =
Cancers are very often '''deficient''' in expression of one or more DNA repair genes, but '''over-expression''' of a DNA repair gene is less usual in cancer. For instance, at least 36 DNA repair enzymes, when mutationally defective in germ line cells, cause increased risk of cancer (hereditary [[cancer syndrome]]s).
=== Interaction with BRCA1 and BRCA2 ===
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=== Application to cancer therapy ===
▲It is hypothesized that [[PARP inhibitor|PARP1 inhibitor]]s 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.<ref name="Bryant_2005">{{cite journal | vauthors = Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T | title = Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase | journal = Nature | volume = 434 | issue = 7035 | pages = 913–7 | date = Apr 2005 | pmid = 15829966 | doi = 10.1038/nature03443 | bibcode = 2005Natur.434..913B }}</ref><ref name="Farmer_2005">{{cite journal | vauthors = 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 | title = Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy | journal = Nature | volume = 434 | issue = 7035 | pages = 917–21 | date = Apr 2005 | pmid = 15829967 | doi = 10.1038/nature03445 | bibcode = 2005Natur.434..917F }}</ref>
===Aging===
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.<ref name="pmid1465394">{{cite journal | vauthors = Grube K, Bürkle A | title = Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span | journal = [[Proceedings of the National Academy of Sciences of the United States of America]] | volume = 89 | issue = 24 | pages = 11759–63 | date =
PARP1 appears to be [[resveratrol]]'s primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).<ref name=Sajish>{{cite journal | vauthors = Sajish M, Schimmel P | title = A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol | journal = [[Nature (journal)|Nature]]
The messenger RNA level and protein level of PARP1 is controlled, in part, by the expression level of the [[ETS1]] transcription factor which interacts with multiple ETS1 binding sites in the promoter region of PARP1.<ref name=Soldatenkov>{{cite journal | vauthors = Soldatenkov VA, Albor A, Patel BK, Dreszer R, Dritschilo A, Notario V | title = Regulation of the human poly(ADP-ribose) polymerase promoter by the ETS transcription factor | journal = [[Oncogene (journal)|Oncogene]] | volume = 18 | issue = 27 | pages = 3954–62 |
Cells from older humans (69 to 75 years of age) have a [[Gene expression#Regulation of gene expression|constitutive]] expression level of both PARP1 and PARP2 genes reduced by half, compared to their levels in young adult humans (19 to 26 years old). However, centenarians (humans aged 100 to 107 years of age) have constitutive expression of PARP1 at levels similar to those of young individuals.<ref name=Chevanne>{{cite journal | vauthors = Chevanne M, Calia C, Zampieri M, Cecchinelli B, Caldini R, Monti D, Bucci L, Franceschi C, Caiafa P | display-authors = 6 | title = Oxidative DNA damage repair and parp 1 and parp 2 expression in Epstein-Barr virus-immortalized B lymphocyte cells from young subjects, old subjects, and centenarians | journal = [[Rejuvenation
Both [[sirtuin 1]] and PARP1 have a roughly equal affinity for the NAD+ that both enzymes require for activity.<ref name="pmid28417163">{{cite journal | vauthors = Hwang ES, Song SB | title = Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells | journal = [[Cellular and Molecular Life Sciences]] | volume = 74 | issue = 18 | pages = 3347–3362 | date=2017 | doi = 10.1007/s00018-017-2527-8 | pmid = 28417163| s2cid = 25896400 | pmc = 11107671 }}</ref> But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.<ref name="pmid28417163" />
== Plant PARP1 ==▼
Plants have a PARP1 with substantial similarity to animal PARP1, and roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied.<ref>{{cite journal | vauthors = Briggs AG, Bent AF | title = Poly(ADP-ribosyl)ation in plants | journal = Trends in Plant Science | volume = 16 | issue = 7 | pages = 372–80 | date = July 2011 | pmid = 21482174 | doi = 10.1016/j.tplants.2011.03.008 }}</ref><ref>{{cite journal | vauthors = Feng B, Liu C, Shan L, He P | title = Protein ADP-Ribosylation Takes Control in Plant-Bacterium Interactions | journal = PLoS Pathogens | volume = 12 | issue = 12 | pages = e1005941 | date = December 2016 | pmid = 27907213 | pmc = 5131896 | doi = 10.1371/journal.ppat.1005941 }}</ref> Intriguingly, in <i>Arabidopsis thaliana</i> (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.<ref name=Song2015>{{cite journal | vauthors = Song J, Keppler BD, Wise RR, Bent AF | title = PARP2 Is the Predominant Poly(ADP-Ribose) Polymerase in Arabidopsis DNA Damage and Immune Responses | journal = PLoS Genetics | volume = 11 | issue = 5 | pages = e1005200 | date = May 2015 | pmid = 25950582 | pmc = 4423837 | doi = 10.1371/journal.pgen.1005200 }}</ref> 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.<ref name=Song2015 />▼
== Role in cell death ==
Following severe DNA damage, excessive activation of PARP1 can lead to cell death.<ref>{{cite journal | vauthors = Erdélyi K, Bakondi E, Gergely P, Szabó C, Virág L | title = Pathophysiologic role of oxidative stress-induced poly(ADP-ribose) polymerase-1 activation: focus on cell death and transcriptional regulation | journal = Cellular and Molecular Life Sciences | volume = 62 | issue = 7–8 | pages = 751–759 | date = April 2005 | pmid = 15868400 | doi = 10.1007/s00018-004-4506-0 | s2cid = 43817844 }}</ref> Initially, overactivation of the enzyme was linked to apoptotic cell death<ref>{{cite journal | vauthors = Tanaka Y, Yoshihara K, Tohno Y, Kojima K, Kameoka M, Kamiya T | title = Inhibition and down-regulation of poly(ADP-ribose) polymerase results in a marked resistance of HL-60 cells to various apoptosis-inducers | journal = Cellular and Molecular Biology | volume = 41 | issue = 6 | pages = 771–781 | date = September 1995 | pmid = 8535170 | url = https://pubmed.ncbi.nlm.nih.gov/8535170/ }}</ref><ref>{{cite journal | vauthors = Rosenthal DS, Ding R, Simbulan-Rosenthal CM, Vaillancourt JP, Nicholson DW, Smulson M | title = Intact cell evidence for the early synthesis, and subsequent late apopain-mediated suppression, of poly(ADP-ribose) during apoptosis | journal = Experimental Cell Research | volume = 232 | issue = 2 | pages = 313–321 | date = May 1997 | pmid = 9168807 | doi = 10.1006/excr.1997.3536 | doi-access = free }}</ref> but later, PARP1-mediated cell death turned out to show characteristics of necrotic cell death (i.e. early plasma membrane disruption, structural and functional mitochondrial alterations).<ref>{{cite journal | vauthors = Virág L, Scott GS, Cuzzocrea S, Marmer D, Salzman AL, Szabó C | title = Peroxynitrite-induced thymocyte apoptosis: the role of caspases and poly (ADP-ribose) synthetase (PARS) activation | journal = Immunology | volume = 94 | issue = 3 | pages = 345–355 | date = July 1998 | pmid = 9767416 | doi = 10.1046/j.1365-2567.1998.00534.x | pmc = 1364252 }}</ref><ref>{{cite journal | vauthors = Virág L, Salzman AL, Szabó C | title = Poly(ADP-ribose) synthetase activation mediates mitochondrial injury during oxidant-induced cell death | journal = Journal of Immunology | volume = 161 | issue = 7 | pages = 3753–3759 | date = October 1998 | doi = 10.4049/jimmunol.161.7.3753 | pmid = 9759901 | s2cid = 5734113 | url = https://journals.aai.org/jimmunol/article/161/7/3753/7226/Poly-ADP-Ribose-Synthetase-Activation-Mediates }}</ref> These findings provided explanation for previous and subsequent reports demonstrating tissue protective effects of PARP inhibitors and the PARP1 knockout phenotypes in various models of ischemia-reperfusion injury (e.g. in stroke, in the heart and in the gut) where oxidative stress-induced cell death is a central cellular event.<ref>{{cite journal | vauthors = Virág L, Szabó C | title = The therapeutic potential of poly(ADP-ribose) polymerase inhibitors | journal = Pharmacological Reviews | volume = 54 | issue = 3 | pages = 375–429 | date = September 2002 | pmid = 12223530 | doi = 10.1124/pr.54.3.375 | s2cid = 27100634 }}</ref> Later, apoptosis inducing factor (AIF; a misnomer) was identified as a key mediator of the PARP1-mediated regulated necrotic cell death pathway termed parthanatos.<ref>{{cite journal | vauthors = Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL | display-authors = 6 | title = Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor | journal = Science | volume = 297 | issue = 5579 | pages = 259–263 | date = July 2002 | pmid = 12114629 | doi = 10.1126/science.1072221 | bibcode = 2002Sci...297..259Y | s2cid = 22991897 | doi-access = }}</ref>
▲== Plant PARP1 ==
▲Plants have a PARP1 with substantial similarity to animal PARP1, and roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection and other stresses have been studied.<ref>{{cite journal | vauthors = Briggs AG, Bent AF | title = Poly(ADP-ribosyl)ation in plants | journal = [[Trends in Plant Science]] | volume = 16 | issue = 7 | pages = 372–80 | date = July 2011 | pmid = 21482174 | doi = 10.1016/j.tplants.2011.03.008 }}</ref><ref>{{cite journal | vauthors = Feng B, Liu C, Shan L, He P | title = Protein ADP-Ribosylation Takes Control in Plant-Bacterium Interactions | journal =
== Interactions ==
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{{div col|colwidth=10em}}
* [[Aprataxin|APTX]]<ref name=pmid15044383/><ref name="pmid5555565">{{cite journal | vauthors = Morgan HE, Jefferson LS, Wolpert EB, Rannels DE | title = Regulation of protein synthesis in heart muscle. II. Effect of amino acid levels and insulin on ribosomal aggregation | journal = [[The Journal of Biological Chemistry]] | volume = 246 | issue = 7 | pages = 2163–70 | date =
* [[MYBL2]]<ref name="pmid10744766">{{cite journal | vauthors = Cervellera MN, Sala A | title = Poly(ADP-ribose) polymerase is a B-MYB coactivator | journal = [[The Journal of Biological Chemistry]] | volume = 275 | issue = 14 | pages = 10692–6 | date =
* [[RELA]]<ref name="pmid11590148">{{cite journal | vauthors = Hassa PO, Covic M, Hasan S, Imhof R, Hottiger MO | title = The enzymatic and DNA binding activity of PARP-1 are not required for NF-kappa B coactivator function | journal = [[The Journal of Biological Chemistry]] | volume = 276 | issue = 49 | pages = 45588–97 | date =
* [[P53]]<ref name=pmid15044383/><ref name="pmid9565608">{{cite journal | vauthors = Malanga M, Pleschke JM, Kleczkowska HE, Althaus FR | title = Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions | journal = [[The Journal of Biological Chemistry]] | volume = 273 | issue = 19 | pages = 11839–43 | date = May 1998 | pmid = 9565608 | doi = 10.1074/jbc.273.19.11839 | doi-access = free }}</ref>
* [[Polymerase (DNA directed), alpha 1|POLA1]]<ref name="pmid9518481">{{cite journal | vauthors = Dantzer F, Nasheuer HP, Vonesch JL, de Murcia G, Ménissier-de Murcia J | title = Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication | journal = [[Nucleic Acids Research]] | volume = 26 | issue = 8 | pages = 1891–8 | date =
* [[POLA2]]<ref name=pmid9518481/>
* [[XRCC1]]<ref name="pmid15044383">{{cite journal | vauthors = Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF | display-authors = 6 | title = Aprataxin, a novel protein that protects against genotoxic stress | journal = [[Human Molecular Genetics]] | volume = 13 | issue = 10 | pages = 1081–93 | date = May 2004 | pmid = 15044383 | doi = 10.1093/hmg/ddh122 | doi-access = free }}</ref><ref name="pmid9584196">{{cite journal | vauthors = Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G | title = XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage | journal = [[Molecular and Cellular Biology]] | volume = 18 | issue = 6 | pages = 3563–71 | date =
* [[ZNF423]]<ref name="pmid14623329">{{cite journal | vauthors = Ku MC, Stewart S, Hata A | title = Poly(ADP-ribose) polymerase 1 interacts with OAZ and regulates BMP-target genes | journal = [[Biochemical and Biophysical Research Communications]] | volume = 311 | issue = 3 | pages = 702–7 | date =
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== Further reading ==
* {{cite journal |
{{PDB Gallery|geneid=142}}
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