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Review
doi: 10.3390/cells9010041.

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

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Review

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Simonetta Pazzaglia et al. Cells..

Abstract

PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

Keywords: DNA repair; PARP; PARP inhibitors; inflammation; tumor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
PARP-1 (poly(ADP-ribose)-polymerase 1) plays a role in multiple DNA damage recognition and repair pathways. BER, base excision repair; NER, nucleotide excision repair; MMR, mismatch repair; HR, homologous recombination; MMEJ, microhomology-mediated end-joining; NHEJ, non-homologous end-joining; cNHEJ, classical non-homologous end-joining; aNHEJ, alternative non-homologous end-joining.
Figure 2
Figure 2
PARP-1 is ubiquitously expressed and plays a central role in inflammation (orange hexagons). By activating NF-κB through several mechanisms (and also NFAT and AP1), PARP-1 induces the production of inflammatory (TNFα, IL1β and others) and effector T cell cytokines (IL4, IL5). Inflammatory mediators activated by PARP-1 include metalloproteinases (MMP9), inducible nitric-oxide synthase (iNOS), several chemokines, prostaglandins (PGE2) and alarmins (HMGB1). It also favors cell recruitment through upregulation of adhesion molecules, including selectins and cell adhesion molecules (ICAM, Intercellular Cell Adhesion Molecule; VCAM, Vascular Cell Adhesion Molecule). When over-activated, PARP-1 also induces cell death and tissue damage, further fueling the inflammatory process. On the other side, PARP-1 inhibits the expression of Foxp3, a transcription factor required for regulatory T cell differentiation and function, and of IL10, an inhibitory cytokine (green hexagon).
Figure 3
Figure 3
Schematic representation of the effects of PARP inhibition on cancer and inflammatory-related diseases. PARP inhibition reduces NF-κB activation and inflammation, with beneficial effects in inflammatory diseases and cancer. Yet, inhibition of DNA damage recognition and repair, although beneficial in cancer therapy, might increase cancer risk.
See this image and copyright information in PMC

References

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