Tumor suppressor p53 represses transcription of RECQ4 helicase
Tumor suppressor p53 represses transcription of RECQ4 helicase
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DOI：
10.1038/sj.onc.1208380
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发表时间：
2005-03-03
期刊：
影响因子：
8
通讯作者：
Harris, CC
中科院分区：
文献类型：
--
作者：
Sengupta, S;Shimamoto, A;Harris, CC
RECQ 4是RecQ解旋酶家族的成员，其参与DNA复制、重组和修复的调节。p53调节包括BLM和WRN的RecQ解旋酶的功能。在这项研究中，我们证明了p53可以调节RECQ 4的转录。使用非转化的，永生化的正常人成纤维细胞，我们表明，RECQ 4表达的p53依赖性下调发生在G1期阻滞的细胞，无论是在存在或不存在外源性DNA损伤。野生型p53（但不是肿瘤衍生的突变形式）抑制RECQ 4启动子活性。喜树碱或依托泊苷依赖性p53介导的抑制被组蛋白去乙酰化酶（HDAC）抑制剂阿司他丁A（TSA）减弱。RECQ 4启动子的抑制伴随着HDAC 1积累的增加，以及SP1和p53与启动子结合的丧失。喜树碱依赖性p53-SP1复合物的同时形成表明其发生在RECQ 4启动子之外。这些数据表明，p53介导的抑制RECQ 4的转录在DNA损伤的结果从转录激活因子和抑制因子的启动子占用的调制。
RECQ4 is a member of the RecQ helicase family, which has been implicated in the regulation of DNAreplication, recombination and repair. p53 modulates the functions of RecQ helicases including BLM and WRN. In this study, we demonstrate that p53 can regulate the transcription of RECQ4. Using nontransformed, immortalized normal human fibroblasts, we show that p53-dependent downregulation of RECQ4 expression occurred in G1-arrested cells, both in the absence or presence of exogenous DNA damage. Wild-type p53 ( but not the tumor-derived mutant forms) repressed RECQ4 promoter activity. The camptothecin or etoposide-dependent p53-mediated repression was attenuated by trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs). Repression of the RECQ4 promoter was accompanied with an increased accumulation of HDAC1, and the loss of SP1 and p53 binding to the promoter. The simultaneous formation of a camptothecin-dependent p53-SP1 complex indicated its occurrence outside of the RECQ4 promoter. These data suggest that p53-mediated repression of RECQ4 transcription during DNA damage results from the modulation of the promoter occupancy of transcription activators and repressors.