Research ArticleLiver Cancer

S-Nitrosylation from GSNOR Deficiency Impairs DNA Repair and Promotes Hepatocarcinogenesis

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Science Translational Medicine  17 Feb 2010:
Vol. 2, Issue 19, pp. 19ra13
DOI: 10.1126/scitranslmed.3000328

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Human hepatocellular carcinoma (HCC) is associated with elevated expression of inducible nitric oxide synthase (iNOS), but the role of nitric oxide in the pathogenesis of HCC remains unknown. We found that the abundance and activity of S-nitrosoglutathione reductase (GSNOR), a protein critical for control of protein S-nitrosylation, were significantly decreased in ~50% of patients with HCC. GSNOR-deficient mice were very susceptible to spontaneous and carcinogen-induced HCC. During inflammatory responses, the livers of GSNOR-deficient mice exhibited substantial S-nitrosylation and proteasomal degradation of the key DNA repair protein O6-alkylguanine-DNA alkyltransferase. As a result, repair of carcinogenic O6-alkylguanines in GSNOR-deficient mice was significantly impaired. Predisposition to HCC, S-nitrosylation and depletion of alkylguanine-DNA alkyltransferase, and accumulation of O6-alkylguanines were all abolished in mice deficient in both GSNOR and iNOS. Thus, our data suggest that GSNOR deficiency, through dysregulated S-nitrosylation, may promote HCC, possibly by inactivating a DNA repair system.


  • Citation: W. Wei, B. Li, M. A. Hanes, S. Kakar, X. Chen, L. Liu, S-Nitrosylation from GSNOR Deficiency Impairs DNA Repair and Promotes Hepatocarcinogenesis. Sci. Transl. Med. 2, 19ra13 (2010).

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