PARP1

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD⁺ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an

• By using NAD+ to synthesize poly ADP ribose (PAR) and transferring PAR moieties to proteins (ADP-ribosylation).^[8]
• 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]}
• Induction of inflammation.^[9]
• The pathophysiology of
  type I diabetes.^[10]

• gastric cancer.^[11]

PARP1 acts as a first responder that detects DNA damage and then facilitates choice of repair pathway.^[12] 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.^[6] 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.^[12]

PARP1 has a role in repair of single-stranded DNA (ssDNA) breaks. Knocking down intracellular PARP1 levels with

PARP1 is required for NF-κB transcription of proinflammatory mediators such as tumor necrosis factor, interleukin 6, and inducible nitric oxide synthase.^[9][18] PARP1 activity contributes to the proinflammatory macrophages that increase with age in many tissues.^[19] ADP-riboyslation of the HMGB1 high-mobility group protein by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation.^[20]

In asthma PARP1 facilitates recruitment and function of immune cells, including CD4+ T-cells, eosinophils, and dendritic cells.^[18]

Over-expression in cancer

PARP1 is one of six enzymes required for the highly error-prone DNA repair pathway microhomology-mediated end joining (MMEJ).^[21] 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.^[22] PARP1 is up-regulated and MMEJ is increased in tyrosine kinase-activated leukemias.^[22]

PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,^[23] BRCA-mutated ovarian cancer,^[24] and BRCA-mutated serous ovarian cancer.^[25]

PARP1 is also over-expressed in a number of other cancers, including neuroblastoma,^[26] HPV infected oropharyngeal carcinoma,^[27] testicular and other germ cell tumors,^[28] Ewing's sarcoma,^[29] malignant lymphoma,^[30] breast cancer,^[31] and colon cancer.^[32]

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

PARP1 appears to be resveratrol's primary functional target through its interaction with the tyrosyl tRNA synthetase (TyrRS).^[40] Tyrosyl tRNA synthetase translocates to the nucleus under stress conditions stimulating NAD⁺-dependent auto-poly-ADP-ribosylation of PARP1,^[40] thereby altering the functions of PARP1 from a chromatin architectural protein to a DNA damage responder and transcription regulator.^[41]

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.^[42] 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.^[23] If these CpG islands in ETS1 binding sites of the PARP1 promoter are epigenetically hypomethylated, PARP1 is expressed at an elevated level.^[23][24]

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.^[43] This high level of PARP1 expression in centenarians was shown to allow more efficient repair of H₂O₂ sublethal oxidative DNA damage.^[43] 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.^[43]

Both sirtuin 1 and PARP1 have a roughly equal affinity for the NAD+ that both enzymes require for activity.^[44] But DNA damage can increase levels of PARP1 more than 100-fold, leaving little NAD+ for SIRT1.^[44]

Role in cell death

Following severe DNA damage, excessive activation of PARP1 can lead to cell death.^[45] Initially, overactivation of the enzyme was linked to apoptotic cell death^[46][47] 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).^[48][49] 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.^[50] Later, apoptosis inducing factor (AIF; a misnomer) was identified as a key mediator of the PARP1-mediated regulated necrotic cell death pathway termed parthanatos.^[51]

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.^[52][53] Intriguingly, in Arabidopsis thaliana (and presumably other plants), PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.^[54] 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.^[54]

Interactions

PARP1 has been shown to

See also

• 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

References