Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8IXL6 (RNS)
 1,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arsenic, a widely distributed carcinogen, is known to significantly amplify the impact of other carcinogens through inhibition of DNA repair. Our recent work suggests that reactive oxygen/nitrogen species (ROS/RNS) induced by arsenite (AsIII) play an important role in the inhibition of the DNA repair protein Poly(ADP-ribose) polymerase 1 (PARP-1). AsIII-induced ROS lead to oxidation of cysteine residues within the PARP-1 zinc finger DNA binding domain. However, the mechanism underlying RNS-mediated PARP inhibition by arsenic remains unknown. In this work, we demonstrate that AsIII treatment of normal human keratinocyte (HEKn) cells induced S-nitrosation on cysteine residues of PARP-1 protein, in a similar manner to a nitric oxide donor. S-nitrosation of PARP-1 could be reduced by 1400W (inducible nitric oxide synthase inhibitor) or c-PTIO (a nitric oxide scavenger). Furthermore, AsIII treatment of HEKn cells leads to zinc loss and inhibition of PARP-1 enzymatic activity. AsIII and 1400W/c-PTIO co-treatment demonstrate that these effects occur in an iNOS- and NO-dependent manner. Importantly, we confirmed S-nitrosation on the zinc finger DNA binding domain of PARP-1 protein. Taken together, AsIII induces S-nitrosation on PARP-1 zinc finger DNA binding domain by generating NO through iNOS activation, leading to zinc loss and inhibition of PARP-1 activity, thereby increasing retention of damaged DNA. These findings identify S-nitrosation as an important component of the molecular mechanism underlying AsIII inhibition of DNA repair, which may benefit the development of preventive and intervention strategies against AsIII co-carcinogenesis.
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PMID:S-nitrosation on zinc finger motif of PARP-1 as a mechanism of DNA repair inhibition by arsenite. 2774 21

Arsenic, in the trivalent form (AsIII), is a human co-carcinogen reported to enhance mutagenesis effects of other carcinogens such as UV radiation by inhibiting DNA repair. The zinc finger DNA repair protein Poly (ADP-ribose) polymerase 1 (PARP-1) is a sensitive target of AsIII and both reactive oxygen and nitrogen species (ROS/RNS) generated by AsIII contribute to PARP-1 inhibition. However, the mechanisms of ROS/RNS-mediated PARP inhibition and how AsIII-generated ROS/RNS may be interconnected are still unclear. In this study, we found AsIII exposure of normal human keratinocyte (HEKn) cells generated peroxynitrite through superoxide and nitric oxide production in an AsIII concentration dependent manner. Peroxynitrite inhibited PARP-1 activity and caused zinc loss from PARP-1 protein while scavenging peroxynitrite was protective of the impacts on PARP-1. We identified peroxynitrite was responsible for S-nitrosation on cysteine residues resulting in PARP-1 zinc finger conformational changes. Taken together, the evidence indicates AsIII generates peroxynitrite through superoxide and nitric oxide production, induces S-nitrosation on PARP-1, leading to zinc loss and activity inhibition of PARP-1, thus enhancing DNA damage caused by UV radiation. These findings highlight a role for peroxynitrite as a key molecule of ROS/RNS mediated DNA repair inhibition by AsIII which should inform the development of prevention and intervention strategies against AsIII co-carcinogenesis.
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PMID:Peroxynitrite contributes to arsenic-induced PARP-1 inhibition through ROS/RNS generation. 3115 18

Exposure to arsenic in contaminated drinking water is an emerging public health problem that impacts more than 200 million people worldwide. Accumulating lines of evidence from epidemiological studies revealed that chronic exposure to arsenic can result in various human diseases including cancer, type 2 diabetes, and neurodegenerative disorders. Arsenic is also classified as a Group I human carcinogen. In this review, we survey extensively different modes of action for arsenic-induced carcinogenesis, with focus being placed on arsenic-mediated impairment of DNA repair pathways. Inorganic arsenic can be bioactivated by methylation, and the ensuing products are highly genotoxic. Bioactivation of arsenicals also elicits the production of reactive oxygen and nitrogen species (ROS and RNS), which can directly damage DNA and modify cysteine residues in proteins. Results from recent studies suggest zinc finger proteins as crucial molecular targets for direct binding to As3+ or for modifications by arsenic-induced ROS/RNS, which may constitute a common mechanism underlying arsenic-induced perturbations of DNA repair.
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PMID:Molecular Mechanisms of Arsenic-Induced Disruption of DNA Repair. 3198 75