The role of the retinoblastoma/E2F1 tumor suppressor pathway in the lesion recognition step of nucleotide excision repair
The role of the retinoblastoma/E2F1 tumor suppressor pathway in the lesion recognition step of nucleotide excision repair
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DOI：
10.1016/j.dnarep.2009.03.003
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发表时间：
2009-07-04
期刊：
影响因子：
3.8
通讯作者：
Ford, James M.
中科院分区：
文献类型：
--
作者：
Lin, Patrick S.;McPherson, Lisa A.;Ford, James M.
视网膜母细胞瘤Rb/E2 F肿瘤抑制通路在调节哺乳动物细胞周期进程中起主要作用。pRb蛋白与密切相关的蛋白质p107和p130沿着，通过与已知在整个细胞周期中调节必需基因的转录因子E2 F家族结合而发挥其抗增殖作用。我们试图研究Rb/E2 F1通路在小鼠胚胎成纤维细胞（MEFs）中核苷酸切除修复（NER）损伤识别步骤中的作用。Rb-/-、p107-/-、p130-/- MEFs修复环丁烷嘧啶二聚体（CPD）和6-4光产物（6-4PPs）的效率高于野生型细胞。参与DNA损伤识别步骤的受损DNA结合基因DDB 2的表达在Rb家族缺陷的MEFs中升高。为了确定在Rb基因家族不存在的情况下增强的DNA修复是否是由于E2 F1的去阻遏，我们测定了E2 F1缺陷细胞修复受损DNA的能力，并证明E2 F1-/- MEFs因去除CPD和6- 4PP而受损。此外，野生型细胞诱导更高的DDB 2和着色性干皮病基因XPC转录水平的表达比E2 F1-/-细胞后UV-C照射。使用E2 F SiteScan算法，我们在转录起始位点上游的XPC启动子中发现了一个推定的E2 F响应元件。我们用染色质免疫沉淀试验表明E2 F1以UV依赖的方式与XPC启动子结合，表明E2 F1是XPC的转录调节因子。我们的研究确定了一个新的E2 F1基因靶点，并进一步支持了越来越多的证据表明，Rb/E2 F1肿瘤抑制途径参与了核苷酸切除修复的DNA损伤识别步骤的调节。(C)2009爱思唯尔有限公司版权所有。
The retinoblastoma Rb/E2F tumor suppressor pathway plays a major role in the regulation of mammalian cell cycle progression. The pRb protein, along with closely related proteins p107 and p130, exerts its anti-proliferative effects by binding to the E2F family of transcription factors known to regulate essential genes throughout the cell cycle. We sought to investigate the role of the Rb/E2F1 pathway in the lesion recognition step of nucleotide excision repair (NER) in mouse embryonic fibroblasts (MEFs). Rb-/-, p107-/-, p130-/- MEFs repaired both cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) at higher efficiency than did wildtype cells following UV-C irradiation. The expression of damaged DNA binding gene DDB2 involved in the DNA lesion recognition step was elevated in the Rb family-deficient MEFs. To determine if the enhanced DNA repair in the absence of the Rb gene family is due to the derepression of E2F1, we assayed the ability of E2F1-deficient cells to repair damaged DNA and demonstrated that E2F1-/- MEFs are impaired for the removal of both CPDs and 6-4PPs. Furthermore, wildtype cells induced a higher expression of DDB2 and xeroderma pigmentosum gene XPC transcript levels than did E2F1-/- cells following UV-C irradiation. Using an E2F SiteScan algorithm, we uncovered a putative E2F-esponsive element in the XPC promoter upstream of the transcription start site. We showed with chromatin immunoprecipitation assays the binding of E2F1 to the XPC promoter in a UV-dependent manner, suggesting that E2F1 is a transcriptional regulator of XPC. Our study identifies a novel E2F1 gene target and further supports the growing body of evidence that the Rb/E2F1 tumor suppressor pathway is involved in the regulation of the DNA lesion recognition step of nucleotide excision repair. (C) 2009 Elsevier B.V. All rights reserved.