Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor
Expression of MCM10 and TopBP1 is regulated by cell proliferation and UV irradiation via the E2F transcription factor
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DOI：
10.1038/sj.onc.1207829
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发表时间：
2004-08-19
期刊：
影响因子：
8
通讯作者：
Inoue, I
中科院分区：
文献类型：
--
作者：
Yoshida, K;Inoue, I
MCM 10和TopBP 1通过调节DNA聚合酶加载因子CDC 45的染色质结合在DNA复制的起始中起作用。TopBP 1也被称为DNA损伤反应蛋白。在这项研究中，我们发现，人MCM 10和TopBP 1的转录激活转录因子E2 F1 -3，但不是由因子E2 F4 -7。对各种MCM 10和TopBP 1启动子构建体的分析表明，在转录起始位点附近的E2 F响应序列对于E2 F1诱导的MCM 10和TopBP 1基因转录的激活是必需的，这进一步被pRb抑制。人MCM 10和TopBP 1的启动子活性被证明是通过E2 F响应序列的生长依赖性的。尽管E2 F1通过紫外线（UV）照射而稳定，但TopBP 1的mRNA表达水平在HCT 116人二倍体结肠癌细胞中被抑制。我们表明，通过进行染色质免疫沉淀，在响应于UV照射，但不是阿霉素处理，E2 F4积累的MCM 10和TopBP 1启动子。我们的数据表明，紫外线照射诱导的DNA损伤的模型依赖于，至少部分地，在MCM 10和TopBP 1启动子，这导致抑制DNA复制的E2 F4转录因子的积累。
MCM10 and TopBP1 function in the initiation of DNA replication, by regulating the chromatin binding of the DNA polymerase a loading factor, CDC45. TopBP1 is also known as a DNA damage response protein. In this study, we showed that the transcription of human MCM10 and TopBP1 is activated by transcription factors E2F1-3, but not by factors E2F4-7. Analysis of various MCM10 and TopBP1 promoter constructs showed that an E2F-responsive sequence in the vicinity of the transcription initiation site is necessary for the E2F1-induced activation of MCM10 and TopBP1 gene transcription, which is further suppressed by pRb. The promoter activities of human MCM10 and TopBP1 were demonstrated to be growth dependent via the E2F-responsive sequence. Although E2F1 was stabilized by ultraviolet (UV) irradiation, the mRNA expression level of TopBP1 was suppressed in HCT116 human diploid colon cancer cells. We showed, by performing chromatin immunoprecipitation that, in response to UV irradiation but not doxorubicin treatment, E2F4 accumulated on the MCM10 and TopBP1 promoters. Our data suggest a model in which UV irradiation-induced DNA damage depends, at least in part, on the accumulation of the E2F4 transcription factor on the MCM10 and TopBP1 promoters, which results in suppression of DNA replication.