Regulation of DNA repair by S-nitrosylation.

Chi-Hui Tang, Wei Wei, Limin Liu

The Department of Microbiology and Immunology, University of California, San Francisco, CA, United States.

Biochimica et biophysica acta 2012 Jun

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Expression of the inducible nitric oxide synthase (iNOS) is commonly induced in inflammation, an important risk factor of cancer. Nitric oxide (NO) and related reactive nitrogen species can directly cause DNA damage to increase DNA mutation. They can also indirectly affect DNA mutation by modulation of DNA repair proteins, in particular through protein S-nitrosylation, a key regulatory mechanism of NO. Here we review protein targets, molecular mechanisms, and potential roles of NO in the regulation of DNA repair, with a focus on S-nitrosylation of DNA repair proteins by endogenous NO synthase activity. Recent studies have identified a number of key DNA repair proteins as targets of S-nitrosylation, including O(6)-alkylguanine-DNA-alkyltransferase (AGT), 8-oxoguanine glycosylase, apurinic-apyrimidinic endonuclease 1, and DNA-dependent protein kinase catalytic subunit. S-nitrosylation has been shown to modulate the activity, stability, and cellular localization of DNA repair proteins. The level of protein S-nitrosylation depends both on NO synthesis by NO synthases and on denitrosylation by a major denitrosylase, S-nitrosoglutathione reductase (GSNOR). Dysregulated S-nitrosylation of AGT due to GSNOR deficiency inactivates AGT-dependent DNA repair and appears to contribute critically to hepatocarcinogenesis. Studies on the S-nitrosylation of DNA repair proteins have started to reveal molecular mechanisms for the contribution of inflammation to mutagenesis and carcinogenesis. The modulation of protein S-nitrosylation to affect the activity of DNA repair proteins may provide a therapeutic strategy to prevent DNA damage and mutation frequently associated with chronic inflammation and to sensitize cancer cells to DNA-damaging drugs. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation. Copyright © 2011 Elsevier B.V. All rights reserved.