Pivotal role for S-nitrosylation of DNA methyltransferase in epigenetic regulation

DNMTs catalyze the methylation of cytosine with SAM. DNA methylation affects key cellular processes by regulating gene expression, thus serving a variety of physiological and pathophysiological roles. However, the chemical mechanisms of DNA methylation by which its enzymatic activity is regulated have not been fully elucidated. We found that a critical cysteine residue in DNMT is the target of protein S-nitrosylation, leading to the attenuation of DNMT enzymatic activity and consequent aberrant regulation of gene expression during neoplastic cell proliferation. Our results demonstrate that de novo DNA methylation mediated by DNMT3 is regulated by NO, which is involved in tumor formation.

DNA甲基转移酶（DNMTs）以S-腺苷甲硫氨酸（SAM）为甲基供体催化胞嘧啶的甲基化修饰。DNA甲基化通过调控基因表达影响诸多关键细胞进程，因此在多种生理及病理生理过程中发挥重要功能。然而，调控DNA甲基转移酶酶活性的DNA甲基化化学机制尚未完全阐明。本研究发现，DNMTs中存在一个关键半胱氨酸残基，可作为蛋白质S-亚硝基化的修饰靶点，该修饰会削弱DNMTs的酶活性，进而在肿瘤细胞增殖过程中引发基因表达的异常调控。我们的实验结果证实，由DNMT3介导的从头DNA甲基化过程可被一氧化氮（NO）调控，而该调控通路参与肿瘤发生过程。