BBA Gene Regulatory Mechanisms:揭示人核糖核苷酸还原酶新的调控机制

摘要 : 近日，国际著名学术期刊《BBA-Gene Regulatory Mechanisms》在线发表了邵吉民教授课题组的研究成果：“ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG”揭示人核糖核苷酸还原酶新的调控机制。论文第一作者为浙江大学医学院2012级硕士生宫朝举，并由博士生刘鸿和硕士生宋锐等合作完成。

近日，国际著名学术期刊《BBA-GENE Regulatory Mechanisms》在线发表了邵吉民教授课题组的研究成果：“ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG”揭示人核糖核苷酸还原酶新的调控机制。论文第一作者为浙江大学医学院2012级硕士生宫朝举，并由博士生刘鸿和硕士生宋锐等合作完成。

人核糖核苷酸还原酶(RR)为DNA复制和修复提供dNDPs，是DNA合成限速酶。RR表达和活性为肿瘤细胞增殖所必须。肿瘤大数据库分析和临床样本检测表明，RR亚基蛋白在多种肿瘤中高表达，但RR亚基蛋白在肿瘤中的上调机制尚不清楚。该课题组研究发现，环境致癌物MNNG可以显著激活RR小亚基RRM2基因的表达;促进RRM2蛋白入核参与DNA损伤修复过程;MNNG通过ATR-CHK1-E2F3信号通路同时促进E2F3和NFY结合到RRM2基因启动子激活RRM2基因转录。该文首次揭示了环境致癌物MNNG激活RRM2转录上调的分子机制以及RRM2在维持基因组稳定性中的作用，为阐明RR在肿瘤发生中的作用和机制提供了新的理论依据。

原文链接：

ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG

原文摘要：

N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent and an environmental carcinogen, causes DNA lesions and evencarcinomas. DNA damage responses induced by MNNG activate various DNA repair genes and related signaling pathways. The present study aimed to investigate the regulatory mechanisms of human RR small subunit M2 (hRRM2) in response to MNNG.In this study, we demonstrated that the RRM2 gene was transactivated by MNNG exposure more strongly than the other small subunit, p53R2. The upregulated RRM2 translocated to the nucleus for DNA repair. Further study showed that E2F3 transactivated RRM2 expression by directly binding to its promoter after MNNG exposure. The transactivation was enhanced by the upregulation of NFY, which bound to theRRM2 promoter adjacent to the E2F3 binding site and interacted with E2F3. In response to MNNG treatment, E2F3 accumulated mainly through its phosphorylation at S124 and was dependent on ATR-CHK1 signaling. In comparison, p53R2 played a relatively weaker role in the MNNG-induced DNA damage response, and its transcription was regulated by the ATR-CHK2-E2F1/p53 pathway.We suggest that MNNG-stimulated ATR/CHK1 signaling stabilizes E2F3 by S124 phosphorylation, and then E2F3 together with NFY co-transactivate RRM2expression for DNA repair.We propose a new mechanism for RRM2 regulation to maintain genome stability in response to environmental chemical carcinogens.DOI: 10.1038/mt.2016.7.

DOI: 10.1016/j.bbagrm.2016.02.012

作者：宫朝举

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