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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 An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''PARP1''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. 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+ to synthesize poly ADP ribose (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 * 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, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
in the development and proliferation of
gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
. *


Role in DNA damage repair

PARP1 acts as a first responder that detects DNA damage 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 installat ...
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 and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
s leading to decompaction of
chromatin Chromatin is a complex of DNA and protein found in eukaryote, 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 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. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
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. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
,
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...
, microhomology-mediated end joining,
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 Cell (biology), cellular organi ...
al repair, and
DNA mismatch repair DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, ...
. PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with
siRNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded non-coding RNA molecules, typically 20–24 base pairs in length, similar to microRNA (miRNA), and operating within the RN ...
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 life, living organisms, acting as the most essential part of heredity, biolog ...
, 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 of biological inheritanc ...
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 Cell (biology), cellular organi ...
(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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
in mice using the pun assay. 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 A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
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 family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
transcription of proinflammatory mediators such as
tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
,
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. PARP1 activity contributes to the proinflammatory
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s that increase with age in many tissues. ADP-riboyslation of the
HMGB1 High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the ''HMGB1'' gene. HMG-1 belongs to the high mobility group and contains a HMG-box domain. Funct ...
high-mobility group protein by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation. In
asthma Asthma is a common 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 wh ...
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 and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
s, and
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s.


Over-expression in cancer

PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (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 ...
. 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.) 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 ...
and
BRCA2 ''BRCA2'' and BRCA2 () are human genes and their protein products, 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 associate ...
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 ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, 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

PARP1 inhibitors are being tested for effectiveness in cancer therapy. 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 Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cura ...
, 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 (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
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, 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 DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
. PARP1 appears to be
resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol or polyphenol and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacterium, ba ...
'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 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 DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
). 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. But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.


Role in cell death

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


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 with: * APTX *
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. ...
*
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 tra ...
* P53 *
POLA1 DNA polymerase alpha catalytic subunit is an enzyme that in humans is encoded by the ''POLA1'' gene. Function This gene encodes the p180 catalytic subunit of DNA polymerase α-primase. Pol α has limited processivity and lacks 3′ exonucle ...
*
POLA2 DNA polymerase alpha subunit 2 is an enzyme that in humans is encoded by the ''POLA2'' gene. Interactions POLA2 has been shown to interact with PARP1. See also * DNA Polymerase A DNA polymerase is a member of a family of enzymes that catalyz ...
* XRCC1 * ZNF423


See also

*
DNA damage theory of aging The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of DNA damage (naturally occurring), naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although ...
*
Maximum lifespan Maximum life span (or, for humans, maximum reported age at death) is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the m ...
* Olaparib – a PARP inhibitor * PARP inhibitor class of investigational anti-cancer drugs * Parthanatos * Poly ADP ribose polymerase *
Senescence Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...


References


Further reading

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