PARP1#Aging

PARP1 works:

• By using NAD+ to synthesize poly ADP ribose (PAR) and transferring PAR moieties to proteins (ADP-ribosylation).{{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 }}
• 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 (in a DNA repair context).

PARP1 is involved in:

• Differentiation, proliferation, and tumor transformation
• Normal or abnormal recovery from DNA damage
• May be the site of mutation in Fanconi anemia{{Citation needed|date=January 2010}}
• Induction of inflammation.{{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 }}
• The pathophysiology of type I diabetes.{{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.{{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 = November 2009 | pmid = 19897724 | pmc = 2785281 | doi = 10.1073/pnas.0906753106 | bibcode = 2009PNAS..10619998N | doi-access = free }}
• {{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}}

PARP1 acts as a first responder that detects DNA damage and then facilitates choice of repair pathway.{{cite journal | vauthors = Pascal JM | title = The comings and goings of PARP-1 in response to DNA damage | journal = DNA Repair | volume = 71 | pages = 177–182 | date = November 2018 | pmid = 30177435 | pmc = 6637744 | doi = 10.1016/j.dnarep.2018.08.022 }} PARP1 contributes to repair efficiency by ADP-ribosylation of histones leading to decompaction of chromatin structure, and by interacting with and modifying multiple DNA repair factors. 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 recombinational repair, and DNA mismatch repair.

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),{{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 = August 2008 | pmid = 18603595 | pmc = 2490739 | doi = 10.1093/nar/gkn403 }}{{cite journal | vauthors = Schultz N, Lopez E, Saleh-Gohari N, Helleday T | title = Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination | journal = Nucleic Acids Research | volume = 31 | issue = 17 | pages = 4959–64 | date = September 2003 | pmid = 12930944 | pmc = 212803 | doi = 10.1093/nar/gkg703 }}{{cite journal | vauthors = Waldman AS, Waldman BC | title = Stimulation of intrachromosomal homologous recombination in mammalian cells by an inhibitor of poly(ADP-ribosylation) | journal = Nucleic Acids Research | volume = 19 | issue = 21 | pages = 5943–7 | date = November 1991 | pmid = 1945881 | pmc = 329051 | doi = 10.1093/nar/19.21.5943 }} which has also been observed in vivo in mice using the pun assay.{{cite journal | vauthors = Claybon A, Karia B, Bruce C, Bishop AJ | title = PARP1 suppresses homologous recombination events in mice in vivo | journal = Nucleic Acids Research | volume = 38 | issue = 21 | pages = 7538–45 | date = November 2010 | pmid = 20660013 | pmc = 2995050 | doi = 10.1093/nar/gkq624 }} 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.{{cite journal | vauthors = Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF | title = Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease | journal = Genes & Development | volume = 9 | issue = 5 | pages = 509–20 | date = March 1995 | pmid = 7698643 | doi = 10.1101/gad.9.5.509 | doi-access = free }}

PARP1 is required for NF-κB transcription of proinflammatory mediators such as tumor necrosis factor, interleukin 6, and inducible nitric oxide synthase.{{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 }} PARP1 activity contributes to the proinflammatory macrophages that increase with age in many tissues.{{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 | volume=2 | issue=3 | pages=e200026 | year=2020 | doi = 10.20900/immunometab20200026 | pmc=7409778 | pmid=32774895}} ADP-riboyslation of the HMGB1 high-mobility group protein by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation.{{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=Cells | volume=9 | issue=1 | pages=41 | year=2019 | doi = 10.3390/cells9010041 | pmc=7017201 | pmid=31877876| doi-access=free }}

In asthma PARP1 facilitates recruitment and function of immune cells, including CD4+ T-cells, eosinophils, and dendritic cells.

PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (MMEJ).{{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 & Disease | volume = 6 | issue = 3 | pages = e1697 | date = March 2015 | pmid = 25789972 | pmc = 4385936 | doi = 10.1038/cddis.2015.58 }} MMEJ is associated with frequent chromosome abnormalities such as deletions, translocations, inversions and other complex rearrangements. When PARP1 is up-regulated, MMEJ is increased, causing genome instability.{{cite journal | vauthors = Muvarak N, Kelley S, Robert C, Baer MR, Perrotti D, Gambacorti-Passerini C, Civin C, Scheibner K, Rassool FV | display-authors = 6 | title = c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias | journal = Molecular Cancer Research | volume = 13 | issue = 4 | pages = 699–712 | date = April 2015 | pmid = 25828893 | pmc = 4398615 | doi = 10.1158/1541-7786.MCR-14-0422 }} PARP1 is up-regulated and MMEJ is increased in tyrosine kinase-activated leukemias.

PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,{{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 = BioMed Research International | volume = 2013 | pages = 946268 | year = 2013 | pmid = 23762867 | pmc = 3666359 | doi = 10.1155/2013/946268 | doi-access = free }} BRCA-mutated ovarian cancer,{{cite journal | vauthors = Li D, Bi FF, Cao JM, Cao C, Li CY, Liu B, Yang Q | title = Poly (ADP-ribose) polymerase 1 transcriptional regulation: a novel crosstalk between histone modification H3K9ac and ETS1 motif hypomethylation in BRCA1-mutated ovarian cancer | journal = Oncotarget | volume = 5 | issue = 1 | pages = 291–7 | date = January 2014 | pmid = 24448423 | pmc = 3960209 | doi = 10.18632/oncotarget.1549 }} and BRCA-mutated serous ovarian cancer.{{cite journal | vauthors = Bi FF, Li D, Yang Q | title = Promoter hypomethylation, especially around the E26 transformation-specific motif, and increased expression of poly (ADP-ribose) polymerase 1 in BRCA-mutated serous ovarian cancer | journal = BMC Cancer | volume = 13 | pages = 90 | date = February 2013 | pmid = 23442605 | pmc = 3599366 | doi = 10.1186/1471-2407-13-90 | doi-access = free }}

PARP1 is also over-expressed in a number of other cancers, including neuroblastoma,{{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 = Molecular Cancer Research | volume = 13 | issue = 3 | pages = 470–82 | date = March 2015 | pmid = 25563294 | doi = 10.1158/1541-7786.MCR-14-0337 | doi-access = free }} HPV infected oropharyngeal carcinoma,{{cite journal | vauthors = Liu Q, Ma L, Jones T, Palomero L, Pujana MA, Martinez-Ruiz H, Ha PK, Murnane J, Cuartas I, Seoane J, Baumann M, Linge A, Barcellos-Hoff MH | display-authors = 6 | title = Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End Joining | journal = Clinical Cancer Research | volume = 24 | issue = 23 | pages = 6001–6014 | date = December 2018 | pmid = 30087144 | doi = 10.1158/1078-0432.CCR-18-1346 | doi-access = free }} testicular and other germ cell tumors,{{cite journal | vauthors = Mego M, Cierna Z, Svetlovska D, Macak D, Machalekova K, Miskovska V, Chovanec M, Usakova V, Obertova J, Babal P, Mardiak J | display-authors = 6 | title = PARP expression in germ cell tumours | journal = Journal of Clinical Pathology | volume = 66 | issue = 7 | pages = 607–12 | date = July 2013 | pmid = 23486608 | doi = 10.1136/jclinpath-2012-201088 | s2cid = 535704 }} Ewing's sarcoma,{{cite journal | vauthors = Newman RE, Soldatenkov VA, Dritschilo A, Notario V | title = Poly(ADP-ribose) polymerase turnover alterations do not contribute to PARP overexpression in Ewing's sarcoma cells | journal = Oncology Reports | volume = 9 | issue = 3 | pages = 529–32 | year = 2002 | pmid = 11956622 | doi = 10.3892/or.9.3.529 }} malignant lymphoma,{{cite journal | vauthors = Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T | title = Enhanced expression of poly(ADP-ribose) synthetase gene in malignant lymphoma | journal = American Journal of Hematology | volume = 37 | issue = 4 | pages = 223–7 | date = August 1991 | pmid = 1907096 | doi = 10.1002/ajh.2830370402 | s2cid = 26905918 }} breast cancer,{{cite journal | vauthors = Rojo F, García-Parra J, Zazo S, Tusquets I, Ferrer-Lozano J, Menendez S, Eroles P, Chamizo C, Servitja S, Ramírez-Merino N, Lobo F, Bellosillo B, Corominas JM, Yelamos J, Serrano S, Lluch A, Rovira A, Albanell J | display-authors = 6 | title = Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer | journal = Annals of Oncology | volume = 23 | issue = 5 | pages = 1156–64 | date = May 2012 | pmid = 21908496 | doi = 10.1093/annonc/mdr361 | doi-access = free }} and colon cancer.{{cite journal | vauthors = Dziaman T, Ludwiczak H, Ciesla JM, Banaszkiewicz Z, Winczura A, Chmielarczyk M, Wisniewska E, Marszalek A, Tudek B, Olinski R | display-authors = 6 | title = PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1 | journal = PLOS ONE | volume = 9 | issue = 12 | pages = e115558 | year = 2014 | pmid = 25526641 | pmc = 4272268 | doi = 10.1371/journal.pone.0115558 | bibcode = 2014PLoSO...9k5558D | doi-access = free }}

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 syndromes).{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} (Also see DNA repair-deficiency disorder.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}} (See also Epigenetically reduced DNA repair and cancer.) Ordinarily, deficient expression of a DNA repair enzyme results in increased un-repaired DNA damage which, through replication errors (translesion synthesis), lead to mutations and cancer. However, PARP1 mediated MMEJ repair is highly inaccurate, so in this case, over-expression, rather than under-expression, apparently leads to cancer.

Both BRCA1 and BRCA2 are at least partially necessary for the HR pathway to function. 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.

PARP1 inhibitors are being tested for effectiveness in cancer therapy.{{cite journal | vauthors = Rajman L, Chwalek K, Sinclair DA | title = Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence | journal = Cell Metabolism | volume = 27 | issue=3 | pages = 529–547 |date=2018 | doi = 10.1016/j.cmet.2018.02.011 | pmc =6342515 | pmid = 29514064}} 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.{{cite journal | vauthors = Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T | display-authors = 6 | title = Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase | journal = Nature | volume = 434 | issue = 7035 | pages = 913–7 | date = April 2005 | pmid = 15829966 | doi = 10.1038/nature03443 | bibcode = 2005Natur.434..913B | s2cid = 4391043 }}{{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 | display-authors = 6 | title = Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy | journal = Nature | volume = 434 | issue = 7035 | pages = 917–21 | date = April 2005 | pmid = 15829967 | doi = 10.1038/nature03445 | bibcode = 2005Natur.434..917F | s2cid = 4364706 }}

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.{{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 = December 1992 | pmid = 1465394 | pmc = 50636 | doi = 10.1073/pnas.89.24.11759 | bibcode = 1992PNAS...8911759G | doi-access = free }} 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.{{cite journal | vauthors = Muiras ML, Müller M, Schächter F, Bürkle A | title = Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians | journal = Journal of Molecular Medicine | volume = 76 | issue = 5 | pages = 346–54 | date = April 1998 | pmid = 9587069 | doi = 10.1007/s001090050226 | s2cid = 24616650 }} 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.{{cite journal | vauthors = Lebel M, Lavoie J, Gaudreault I, Bronsard M, Drouin R | title = Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice | journal = The American Journal of Pathology | volume = 162 | issue = 5 | pages = 1559–69 | date = May 2003 | pmid = 12707040 | pmc = 1851180 | doi = 10.1016/S0002-9440(10)64290-3 }} These findings indicate a linkage between longevity and PARP-mediated DNA repair capability. Furthermore, PARP can also act against production of reactive oxygen species, which may contribute to longevity by inhibiting oxidative damage to DNA and proteins.{{cite journal | vauthors = Liu Q, Gheorghiu L, Drumm M, Clayman R, Eidelman A, Wszolek MF, Olumi A, Feldman A, Wang M, Marcar L, Citrin DE, Wu CL, Benes CH, Efstathiou JA, Willers H | display-authors = 6 | title = PARP-1 inhibition with or without ionizing radiation confers reactive oxygen species-mediated cytotoxicity preferentially to cancer cells with mutant TP53 | journal = Oncogene | volume = 37 | issue = 21 | pages = 2793–2805 | date = May 2018 | pmid = 29511347 | pmc = 5970015 | doi = 10.1038/s41388-018-0130-6 }} These observations suggest that PARP activity contributes to mammalian longevity, consistent with the DNA damage theory of aging.{{Citation needed|date=December 2019|reason=removed citation to predatory publisher content}}

PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).{{cite journal | vauthors = Sajish M, Schimmel P | title = A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol | journal = Nature | volume = 519 | issue = 7543 | pages = 370–3 | date = March 2015 | pmid = 25533949 | pmc = 4368482 | doi = 10.1038/nature14028 | bibcode = 2015Natur.519..370S }} Tyrosyl tRNA synthetase translocates to the nucleus under stress conditions stimulating NAD⁺-dependent auto-poly-ADP-ribosylation of PARP1, thereby altering the functions of PARP1 from a chromatin architectural protein to a DNA damage responder and transcription regulator.{{cite journal | vauthors = Muthurajan UM, Hepler MR, Hieb AR, Clark NJ, Kramer M, Yao T, Luger K | title = Automodification switches PARP-1 function from chromatin architectural protein to histone chaperone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 35 | pages = 12752–7 | date = September 2014 | pmid = 25136112 | pmc = 4156740 | doi = 10.1073/pnas.1405005111 | bibcode = 2014PNAS..11112752M | doi-access = free }}

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.{{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 | volume = 18 | issue = 27 | pages = 3954–62 | date = July 1999 | pmid = 10435618 | doi = 10.1038/sj.onc.1202778 | doi-access = free }} The degree to which the ETS1 transcription factor can bind to its binding sites on the PARP1 promoter depends on the methylation status of the CpG islands in the ETS1 binding sites in the PARP1 promoter. If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.

Cells from older humans (69 to 75 years of age) have a 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.{{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 Research | volume = 10 | issue = 2 | pages = 191–204 | date = June 2007 | pmid = 17518695 | doi = 10.1089/rej.2006.0514 |url=https://www.researchgate.net/publication/6313423}} This high level of PARP1 expression in centenarians was shown to allow more efficient repair of H₂O₂ sublethal oxidative DNA damage. Higher DNA repair is thought to contribute to longevity (see DNA damage theory of aging). The high constitutive levels of PARP1 in centenarians were thought to be due to altered epigenetic control of PARP1 expression.

Both sirtuin 1 and PARP1 have a roughly equal affinity for the NAD+ that both enzymes require for activity.{{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 }} But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.

Following severe DNA damage, excessive activation of PARP1 can lead to cell death.{{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 | pmc = 11924491 }} Initially, overactivation of the enzyme was linked to apoptotic cell death{{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/ }}{{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 }} 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).{{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 }}{{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 | url-access = subscription }} 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.{{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 }} Later, apoptosis inducing factor (AIF; a misnomer) was identified as a key mediator of the PARP1-mediated regulated necrotic cell death pathway termed parthanatos.{{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 = }}

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.{{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 }}{{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 | doi-access = free }} Intriguingly, in Arabidopsis thaliana (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.{{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 | doi-access = free }} 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.

PARP1 has been shown to interact with:

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• APTX{{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 = April 1971 | doi = 10.1016/S0021-9258(19)77203-2 | pmid = 5555565 | doi-access = free }}
• MYBL2{{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 = April 2000 | pmid = 10744766 | doi = 10.1074/jbc.275.14.10692 | doi-access = free }}
• RELA{{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 = December 2001 | pmid = 11590148 | doi = 10.1074/jbc.M106528200 | doi-access = free }}
• P53{{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 }}
• POLA1{{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 = April 1998 | pmid = 9518481 | pmc = 147507 | doi = 10.1093/nar/26.8.1891 }}
• POLA2
• XRCC1{{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 }}{{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 = June 1998 | pmid = 9584196 | pmc = 108937 | doi = 10.1128/MCB.18.6.3563 }}
• ZNF423{{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 = November 2003 | pmid = 14623329 | doi = 10.1016/j.bbrc.2003.10.053 }}

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• DNA damage theory of aging
• Maximum lifespan
• Olaparib – a PARP inhibitor
• PARP inhibitor class of investigational anti-cancer drugs
• Parthanatos
• Poly ADP ribose polymerase
• Senescence

{{Reflist|35em}}

• {{cite journal | vauthors = Rosado MM, Bennici E, Novelli F, Pioli C | title = Beyond DNA repair, the immunological role of PARP-1 and its siblings | journal = Immunology | volume = 139 | issue = 4 | pages = 428–37 | date = August 2013 | pmid = 23489378 | pmc = 3719060 | doi = 10.1111/imm.12099}} Review of the subject.

{{PDB Gallery|geneid=142}}

Category:Aging-related enzymes

Category:Aging-related proteins