NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression

Bian, Chunjing; Zhang, Chao; Luo, Tao; Vyas, Aditi; Chen, Shih-Hsun; Liu, Chao; Kassab, Muzaffer Ahmad; Yang, Ying; Kong, Mei; Yu, Xiaochun

doi:10.1038/s41467-019-08530-5

Cited by 48 publications

(49 citation statements)

References 71 publications

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“…Additionally supporting the importance of DNA repair to PR maintenance, Category 01 gene Atr encodes a master regulator of the DNA damage response that has surprisingly been linked to retinal degenerative disease and localized to the cilium [401]. Further, Category 03 gene Nmnat1 encodes an enzyme that synthesizes nicotinamide adenine dinucleotide in the nucleus, which may regulate the large-scale polyADP-ribosylation of protein targets at sites of DNA damage [402]. Mutations in the genes encoding these proteins all result in PR cell loss [230,384,385,400,401,[403][404][405][406][407][408][409][410][411].…”

Section: Category 10: Dna Repair Rna Biogenesis and Protein Modificmentioning

confidence: 96%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.

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Section: Category 10: Dna Repair Rna Biogenesis and Protein Modificmentioning

confidence: 96%

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Collin

Gogna

Chang

et al. 2020

Cells

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“…Blocking PARP1 phosphorylation with a c-Met inhibitor can increase the efficacy of PARP inhibitors (Du et al 2016). Endogenous inhibition of PARP activity through increased levels of NADP + was shown to render ovarian cancer cells hypersensitive to PARP inhibitors irrespective of the BRCA status, suggesting that NADP + levels could also be used as a biomarker of PARP inhibitor sensitivity (Bian et al 2019).…”

Section: Determinants Of Parp Inhibitor Sensitivity In Cancer Cellsmentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

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Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

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“…( iv ) As the NAD + precursor, it further increases its levels. ( v ) The increased concentration of NAD + provides the substrate for NAD + kinase, leading to production of NADP + , which is a stronger PARP inhibitor [ 82 ], thereby strengthening the PARP 1 inhibitory capacity. ( vi ) NADP + which acts by competing with NAD + thus conserving NAD + levels, is able to inhibit various classes of PARP other than PARP1 [ 82 ].…”

Section: Potential Therapies Of Covid-19mentioning

confidence: 99%

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

Badawy

2020

Bioscience Reports

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COVID-19 induces a proinflammatory environment that is stronger in patients requiring intensive care. The cytokine components of this environment may determine efficacy or otherwise of glucocorticoid therapy. The immunity modulators, the aryl hydrocarbon receptor (AhR) and the nuclear NAD+-consuming enzyme poly (ADP-ribose) polymerase 1 (PARP 1) may play a critical role in COVID-19 pathophysiology. The AhR is over-expressed in coronaviruses, including COVID-19 and, as it regulates PARP gene expression, the latter is likely to be activated in COVID-19. PARP 1 activation leads to cell death mainly by depletion of NAD+ and ATP, especially when availability of these energy mediators is compromised. PARP expression is enhanced in other lung conditions: the pneumovirus respiratory syncytial virus (RSV) and chronic obstructive pulmonary disease (COPD). I propose that PARP 1 activation is the terminal point in a sequence of events culminating in patient mortality and should be the focus of COVID-19 immunotherapy. Potent PARP 1 inhibitors are undergoing trials in cancer, but a readily available inhibitor, nicotinamide, which possesses a highly desirable biochemical and activity profile, merits exploration. It conserves NAD+ and prevents ATP depletion by PARP 1 and Sirtuin 1 inhibition, enhances NAD+ synthesis, and hence that of NADP+ which is a stronger PARP inhibitor, reverses lung injury caused by ischaemia/reperfusion, inhibits proinflammatory cytokines, and is effective against HIV infection. These properties qualify nicotinamide for therapeutic use initially in conjunction with standard clinical care or combined with other agents, and subsequently as an adjunct to stronger PARP 1 inhibitors or other drugs.

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NADP+ is an endogenous PARP inhibitor in DNA damage response and tumor suppression

Cited by 48 publications

References 71 publications

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss

PARP and PARG inhibitors in cancer treatment

Immunotherapy of COVID-19 with poly (ADP-ribose) polymerase inhibitors: starting with nicotinamide

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