Poly (ADP-ribose) polymerase

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poly [ADP-ribose] polymerase
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NAD+ ADP-ribosyltransferase
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ADP ribose
Nicotinamide adenine dinucleotide

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.[1]

Members of PARP family

The PARP family comprises 17 members (10 putative).[2] They vary greatly in structure and function within the cell.

Structure

PARP is composed of four domains of interest: a

catalytic domain
. The DNA-binding domain is composed of two zinc finger motifs. In the presence of damaged DNA (base pair-excised), the DNA-binding domain will bind the DNA and induce a conformational shift. It has been shown that this binding occurs independent of the other domains. This is integral in a programmed cell death model based on caspase cleavage inhibition of PARP. The auto-modification domain is responsible for releasing the protein from the DNA after catalysis. Also, it plays an integral role in cleavage-induced inactivation.

Functions

The main role of PARP (found in the cell nucleus) is to detect and initiate an immediate cellular response to metabolic, chemical, or radiation-induced single-strand DNA breaks (SSB) by signaling the enzymatic machinery involved in the SSB repair.

Once PARP detects a SSB, it binds to the

polymeric adenosine diphosphate ribose (poly (ADP-ribose) or PAR) chain, which acts as a signal for the other DNA-repairing enzymes. Target enzymes include DNA ligase III (LigIII), DNA polymerase beta (polβ), and scaffolding proteins such as X-ray cross-complementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via Poly(ADP-ribose) glycohydrolase (PARG).[3]

NAD+ is required as substrate for generating ADP-ribose monomers. It has been thought that overactivation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion and necrotic cell death, since glucose oxidation is inhibited.[4] But more recently it was suggested that inhibition of hexokinase activity leads to defects in glycolysis (Andrabi, PNAS 2014). Basal PARP activity also regulates basal bioenergetics.[5] Note below that PARP is inactivated by caspase-3 cleavage during programmed cell death.

PARP enzymes are essential in a number of cellular functions,[6] including expression of inflammatory genes:[7] PARP1 is required for the induction of ICAM-1 gene expression by cardiac myocytes [8] and smooth muscle cells, in response to TNF.[9]

Activity

The catalytic domain is responsible for Poly (ADP-ribose) polymerization. This domain has a highly conserved motif that is common to all members of the PARP family. PAR polymer can reach lengths of up to 200 nucleotides before inducing apoptotic processes. The formation of PAR polymer is similar to the formation of DNA polymer from nucleoside triphosphates. Normal DNA synthesis requires that a pyrophosphate act as the leaving group, leaving a single phosphate group linking deoxyribose sugars. PAR is synthesized using nicotinamide (NAM) as the leaving group. This leaves a pyrophosphate as the linking group between ribose sugars rather than single phosphate groups. This creates some special bulk to a PAR bridge, which may have an additional role in cell signaling.

Role in repairing DNA nicks

One important function of PARP is assisting in the repair of single-strand DNA nicks. It binds sites with single-strand breaks through its N-terminal zinc fingers and will recruit XRCC1, DNA ligase III, DNA polymerase beta, and a kinase to the nick. This is called base excision repair (BER). PARP-2 has been shown to oligomerize with PARP-1 and, therefore, is also implicated in BER. The oligomerization has also been shown to stimulate PARP catalytic activity. PARP-1 is also known for its role in transcription through remodeling of chromatin by PARylating histones and relaxing chromatin structure, thus allowing transcription complex to access genes.

PARP-1 and PARP-2 are activated by DNA single-strand breaks, and both PARP-1 and PARP-2 knockout mice have severe deficiencies in DNA repair, and increased sensitivity to alkylating agents or ionizing radiation.[10]

PARP activity and lifespan

PARP activity (which is mainly due to PARP1) measured in the permeabilized mononuclear

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,[13]
again indicating a linkage between longevity and repair capability.

These findings suggest that PARP-mediated DNA repair capability contributes to mammalian longevity. Thus, these findings support the DNA damage theory of aging, which assumes that un-repaired DNA damage is the underlying cause of aging, and that DNA repair capability contributes to longevity.[14][15]

Role of tankyrases

The

Mad2 spindle checkpoint
. TNKs can also PARsylate Mcl-1L and Mcl-1S and inhibit both their pro- and anti-apoptotic function; relevance of this is not yet known.

Role in cell death

PARP can be activated in cells experiencing stress and/or DNA damage. Activated PARP can deplete the cell of ATP in an attempt to repair the damaged DNA. ATP depletion in a cell leads to lysis and cell death (necrosis).[16][17] PARP also has the ability to induce programmed cell death, via the production of PAR, which stimulates mitochondria to release AIF.[18] This mechanism appears to be caspase-independent. Cleavage of PARP, by enzymes such as caspases or cathepsins, typically inactivates PARP. The size of the cleavage fragments can give insight into which enzyme was responsible for the cleavage and can be useful in determining which cell death pathway has been activated.

Role in epigenetic DNA modification

CCCTC-binding factor (CTCF) induces PAR accumulation.[19] ADP-ribose polymers, either free or PARP1 bound, are able to inhibit DNA methyltransferase activity at CpG sites.[20] Thus, CTCF is involved in the cross-talk between poly(ADP-ribosyl)ation and DNA methylation, an important epigenetic regulatory factor.[19]

Therapeutic inhibition

A substantial body of preclinical and clinical data has accumulated with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and leading to the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors of various types (e.g. olaparib) for BRCA mutant breast and ovarian cancers can extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. There are several additional classes of novel PARP inhibitors that are in various stages of clinical development.[21]

Another substantial body of data relates to the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock, and acute myocardial infarction), PARP inhibitors exert therapeutic benefit (e.g. reduction of infarct size or improvement of organ function). There are also observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, in a process called "therapeutic repurposing".[22]

Inactivation

PARP is inactivated by caspase cleavage. It is believed that normal inactivation occurs in systems where DNA damage is extensive. In these cases, more energy would be invested in repairing damage than is feasible, so that energy is instead retrieved for other cells in the tissue through programmed cell death. Besides degradation, there is recent evidence about reversible downregulation mechanisms for PARP, among these an "autoregulatory loop", which is driven by PARP1 itself and modulated by the YY1 transcription factor.[23]

While in vitro cleavage by caspase occurs throughout the caspase family, preliminary data suggest that caspase-3 and caspase-7 are responsible for in vivo cleavage. Cleavage occurs at

kDa
and 89 kDa segment. The smaller moiety includes the zinc finger motif requisite in DNA binding. The 89 kDa fragment includes the auto-modification domain and catalytic domain. The putative mechanism of PCD activation via PARP inactivation relies on the separation of the DNA-binding region and the auto-modification domain. The DNA-binding region is capable of doing so independent of the rest of the protein, cleaved or not. It is unable, however, to dissociate without the auto-modification domain. In this way, the DNA-binding domain will attach to a damaged site and be unable to effect repair, as it no longer has the catalytic domain. The DNA-binding domain prevents other, non-cleaved PARP from accessing the damaged site and initiating repairs. This model suggests that this "sugar plug" can also begin the signal for apoptosis.

Plant PARPs

Roles of poly(ADP-ribosyl)ation in plant responses to DNA damage, infection, and other stresses have been studied.[24][25] Plant PARP1 is very similar to animal PARP1, but intriguingly, in Arabidopsis thaliana and presumably other plants, PARP2 plays more significant roles than PARP1 in protective responses to DNA damage and bacterial pathogenesis.[26] The plant PARP2 carries PARP regulatory and catalytic domains with only intermediate similarity to PARP1, and it carries N-terminal SAP DNA binding motifs rather than the zinc finger DNA binding motifs of plant and animal PARP1 proteins.[26]

See also

References

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  3. PMID 20388209
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  4. PMID 8700830
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  6. PMID 19415146
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  7. PMID 17395016
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  8. PMID 9670921
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  9. PMID 17993261
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  10. PMID 15743677
    .
  11. PMID 1465394
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  12. S2CID 37233083
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  13. S2CID 24616650
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  14. ISBN 3-527-30542-4
    .
  15. ISBN 978-1604565812. Archived from the original
    on 2014-10-25. Retrieved 2013-05-10.
  16. S2CID 5734113
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  17. PMID 10570184
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  18. PMID 17116881
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  19. ^
    PMID 18539602
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  20. PMID 12897854
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  21. PMID 23370117
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  22. PMID 28213892
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  23. PMID 22937159
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  24. PMID 21482174
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  25. PMID 27907213
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  26. ^
    PMID 25950582
    .

External links
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