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Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
that in humans is encoded by the ''PARP1''
gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ...
. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.


Function

PARP1 works: * By using
NAD+ Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ad ...
to synthesize poly
ADP ribose Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor ...
(PAR) and transferring PAR moieties to proteins ( 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 (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 Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of nor ...
* Induction of inflammation. * The pathophysiology of type I diabetes. PARP1 is activated by: *
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...
in the development and proliferation of
gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lymp ...
. *


Role in DNA damage repair

PARP1 acts as a first responder that detects
DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA d ...
and then facilitates choice of
repair The technical meaning of maintenance involves functional checks, servicing, repairing or replacing of necessary devices, equipment, machinery, building infrastructure, and supporting utilities in industrial, business, and residential installa ...
pathway. PARP1 contributes to repair efficiency by ADP-ribosylation of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wr ...
s leading to decompaction of
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
structure, and by interacting with and modifying multiple
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolism, metabolic activities and environmental factors such as r ...
factors. PARP1 is implicated in the regulation of several DNA repair processes including the pathways of
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleo ...
, non-homologous end joining,
microhomology-mediated end joining Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ ...
,
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
al 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 In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritance ...
, the
replication fork In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritance ...
stalls, and double-strand DNA (dsDNA) breaks accumulate. These dsDNA breaks are repaired via
homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may be ...
(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), which has also been observed in vivo in mice using the
pun assay A pun, also known as paronomasia, is a form of word play that exploits multiple meanings of a term, or of similar-sounding words, for an intended humorous or rhetorical effect. These ambiguities can arise from the intentional use of homophonic ...
. Thus, if the HR pathway is functioning, PARP1
null mutant A null allele is a nonfunctional allele (a variant of a gene) caused by a genetic mutation. Such mutations can cause a complete lack of production of the associated gene product or a product that does not function properly; in either case, the al ...
s (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.


Role in inflammation

PARP1 is required for
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellula ...
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
of
proinflammatory Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
mediators such as tumor necrosis factor,
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
, and inducible
nitric oxide synthase Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peris ...
. PARP1 activity contributes to the proinflammatory
macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s that increase with age in many tissues. ADP-riboyslation of the HMGB1
high-mobility group High-Mobility Group or HMG is a group of chromosomal proteins that are involved in the regulation of DNA-dependent processes such as transcription, replication, recombination, and DNA repair. Families The HMG proteins are subdivided into 3 sup ...
protein by PARP1 inhibits removal of
apoptotic Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
cells, thereby sustaining inflammation. In
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, ...
PARP1 facilitates recruitment and function of immune cells, including CD4+ T-cells,
eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s, and
dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
s.


Over-expression in cancer

PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway
microhomology-mediated end joining Microhomology-mediated end joining (MMEJ), also known as alternative nonhomologous end-joining (Alt-NHEJ) is one of the pathways for repairing double-strand breaks in DNA. As reviewed by McVey and Lee, the foremost distinguishing property of MMEJ ...
(MMEJ). 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 Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneu ...
. 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, BRCA-mutated ovarian cancer, and BRCA-mutated serous ovarian cancer. PARP1 is also over-expressed in a number of other cancers, including neuroblastoma, HPV infected oropharyngeal carcinoma, testicular and other germ cell tumors, Ewing's sarcoma, malignant lymphoma, breast cancer, and colon cancer. 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). (Also see
DNA repair-deficiency disorder A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair. DNA repair defects can cause an accelerated aging disease or an increased risk of cancer, or sometimes both. DNA repair defects and accelerated ...
.) Similarly, at least 12 DNA repair genes have frequently been found to be epigenetically repressed in one or more cancers. (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.


Interaction with BRCA1 and BRCA2

Both
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
and
BRCA2 ''BRCA2'' and BRCA2 () are a human gene and its protein product, respectively. The official symbol (BRCA2, italic for the gene, nonitalic for the protein) and the official name (originally breast cancer 2; currently BRCA2, DNA repair associated) ...
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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes inclu ...
, 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
xenograft Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograft ...
s from becoming tumors and eradicate tumors having previously formed from BRCA1/2-deficient xenografts.


Application to cancer therapy

PARP1 inhibitors are being tested for effectiveness in
cancer therapy Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
. 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.


Aging

PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mu ...
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. 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. The Wrn protein is deficient in persons with
Werner syndrome Werner syndrome (WS) or Werner's syndrome, also known as "adult progeria",James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. . is a rare, autosomal recessive disord ...
, a human premature aging disorder. PARP1 and Wrn proteins are part of a complex involved in the processing of DNA breaks. 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. These observations suggest that PARP activity contributes to mammalian longevity, consistent with the
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...
. PARP1 appears to be
resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources ...
's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS). 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. 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. 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 The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
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. 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 DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...
). The high constitutive levels of PARP1 in centenarians were thought to be due to altered epigenetic control of PARP1 expression. Both
sirtuin 1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene. SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (''S. cerevisiae''), referring to the fact ...
and PARP1 have a roughly equal affinity for the NAD+ that both enzymes require for activity. But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.


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. Intriguingly, in ''Arabidopsis thaliana'' (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis. 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.


Interactions

PARP1 has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
APTX aptX (''apt'' stands for ''audio processing technology'') is a family of proprietary audio codec compression algorithms owned by Qualcomm, with a heavy emphasis on wireless audio applications. History The original aptX algorithm was develope ...
*
MYBL2 Myb-related protein B is a protein that in humans is encoded by the ''MYBL2'' gene. Function The protein encoded by this gene, a member of the MYB family of transcription factor genes, is a nuclear protein involved in cell cycle progression. T ...
*
RELA Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene. RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tran ...
*
P53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
* POLA1 * POLA2 *
XRCC1 DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the ''XRCC1'' gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III. Function XRCC1 is invo ...
* ZNF423


See also

*
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DN ...
* Maximum lifespan * Olaparib – a PARP inhibitor *
PARP inhibitor PARP inhibitors are a group of pharmacological inhibitors of the enzyme poly ADP ribose polymerase (PARP). They are developed for multiple indications, including the treatment of heritable cancers. Several forms of cancer are more dependent o ...
class of investigational anti-cancer drugs * Parthanatos * Poly ADP ribose polymerase *
Senescence Senescence () or biological aging is the gradual deterioration of functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence invo ...


References


Further reading

* Review of the subject. {{PDB Gallery, geneid=142 Aging-related enzymes Aging-related proteins