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Upon stimulation, the active PARP enzyme acts on its binding partner and results in complex dissociation from DNA.PARP can also exert its effects as an inactive enzyme by directly interacting with and altering transcription factor function. This is seen when acetylated PARP association with NFB results in transcription of its downstream targets. Sumoylation of PARP, however, prevents pCBP from acetylating PARP, hence the loss of coactivator function. Surprisingly, in response to inflammatory stimulation by lipopolysaccharide, PARP loses its repressive function on NFB at different sets of gene promoters when cleaved by inflammasomedependent caspase, enabling transcription of proinflammatory genes. Likewise, increased affinity of PARP for the SMARCB promoter by a single GT   SNP enhanced the SWISNF chromatin remodeling complex transcript and protein expression. In agreement with phenotypes from promoter SNP variant analysis, single base substitutions within the HBV PARP binding motif was sufficient to abrogate transcriptional activation at the viral core promoter. The effect of single base substitutions on promoter transcriptional activity concurred with the ability of PARP to bind the mutant DNA sequence, indicating that the motif through which PARP exerts transcriptional effects is RNNWCAAA, where R is A or G, and W is A or T, and N may be any nucleotide.Motif recognition is heavily reliant on the half of the sequence, especially at nucleotide positions and, as their mutation abrogated transcription and PARP binding.Since BRCA is crucial for dsDB repair by HR, the finding that its expression is regulated by PARP suggests another means through which PARP controls DNA repair.However, the mechanism discriminating between intact binding motifs and damaged DNA remains unknown.The mechanism governing oscillating PARP enzymatic activity is not known, although in mice, autoregulatory loops with PARP acting as a transcriptional repressor at its own promoter may help to achieve this. This intricate balance of PARP functions, however, may be perturbed in disease states such as cancer and inflammation, or by external agents such as small molecule PARP inhibitors and viruses, favoring one function over the other.Synthetic lethality may be achieved with PARP inhibitors designed to compete with NAD for the PARP catalytic site, and these small molecules have produced promising results in clinical trials for the treatment of <a href="http://www.targetmol.com/compound/Rasagiline-Mesylate"></a> several cancers.PARP is also frequently implicated in inflammatory disorders such as sepsis, diabetes, myocardial infarction and stroke, as considerable bystander DNA damage resulting from the generation of reactive oxygen species hyperactivates PARP.Large amounts of NAD consumed in the process can also result in necrosis, aggravating the inflammatory condition.Under such circumstances, treatment with PARP inhibitors can provide symptomatic relief in animal models for such diseases, raising hope for clinical efficacy in the near future.Sequencedependent PARP binding for SNP variants within promoter elements of the cytokine IL, have all been associated with systemic lupus erythematosus, respectively.The effect of PARP inhibition on the outcome of such diseases, however, has not been evaluated.Importantly, because both PARP DNA repair and transcription factor functions may be implicated, the outcome of enzymatic inhibition in certain diseases need not be immediately conclusive.Whether this may also be true in the clinical setting remains to be seen.HBV is one external agent which deprives the infected host cell of PARP activity for its efficient replication whilst preventing its function in DNA repair, as the PARP binding motif ACTTCAAA carried within its genome is readily recognizable for transcriptional activation.

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