ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG
ATR-CHK1-E2F3 signaling transactivates human ribonucleotide reductase small subunit M2 for DNA repair induced by the chemical carcinogen MNNG
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ATR-CHK1-E2F3 信号反式激活人核糖核苷酸还原酶小亚基 M2，用于化学致癌物 MNNG 诱导的 DNA 修复
DOI：
10.1016/j.bbagrm.2016.02.012
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发表时间：
2016-04-01
影响因子：
4.7
通讯作者：
Shao, Jimin
中科院分区：
文献类型：
--
作者：
Gong, Chaoju;Liu, Hong;Shao, Jimin
背景：N-甲基-N '-硝基-N-亚硝基胍（MNNG）是一种烷化剂，也是一种环境致癌物，可引起DNA损伤甚至癌变。MNNG诱导的DNA损伤反应激活了多种DNA修复基因和相关信号通路。本研究旨在探讨人RR小亚基M2（hRRM 2）对MNNG应答的调控机制。结果：MNNG对RRM 2基因的反式激活作用强于另一个小亚基p53 R2。上调的RRM 2易位到细胞核进行DNA修复。进一步的研究表明，MNNG暴露后，E2 F3通过直接结合其启动子反式激活RRM 2的表达。NFY的上调增强了反式激活，NFY结合到邻近E2 F3结合位点的RRM 2启动子上并与E2 F3相互作用。MNNG处理后，E2 F3主要通过其在S124的磷酸化积累，并依赖于ATR-CHK 1信号。结论：MNNG诱导的ATR/CHK 1信号通路通过5124磷酸化稳定E2 F3，E2 F3和NFY共同反式激活RRM 2的表达，从而促进DNA修复。一般意义：我们提出了一种新的RRM 2调节机制，以维持基因组的稳定性，以应对环境化学致癌物。(C)2016爱思唯尔B. V.保留所有权利。
Background: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), an alkylating agent and an environmental carcinogen, causes DNA lesions and even carcinomas. 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.Results: 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 the RRM2 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.Conclusions: We suggest that MNNG-stimulated ATR/CHK1 signaling stabilizes E2F3 by 5124 phosphorylation, and then E2F3 together with NFY co-transactivate RRM2 expression for DNA repair. General significance: We propose a new mechanism for RRM2 regulation to maintain genome stability in response to environmental chemical carcinogens. (C) 2016 Elsevier B.V. All rights reserved.