Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3752-7. doi: 10.1073/pnas.0914818107. Epub 2010 Feb 2.
An essential step in the pathogenesis of human papillomavirus (HPV)-associated cancers is the dysregulated expression of the viral oncogenes. The papillomavirus E2 protein can silence the long control region (LCR) promoter that controls viral E6 and E7 oncogene expression. The mechanisms by which E2 represses oncogene expression and the cellular factors through which E2 mediates this silencing are largely unknown. We conducted an unbiased, genome-wide siRNA screen and series of secondary screens that identified 96 cellular genes that contribute to the repression of the HPV LCR. In addition to confirming a role for the E2-binding bromodomain protein Brd4 in E2-mediated silencing, we identified a number of genes that have not previously been implicated in E2 repression, including the demethylase JARID1C/SMCX as well as EP400, a component of the NuA4/TIP60 histone acetyltransferase complex. Each of these genes contributes independently and additively to E2-mediated silencing, indicating that E2 functions through several distinct cellular complexes to repress E6 and E7 expression.
人乳头瘤病毒（HPV）相关癌症发病机制中的一个重要步骤是病毒癌基因的失调表达。乳头瘤病毒 E2 蛋白可以沉默控制病毒 E6 和 E7 癌基因表达的长控制区（LCR）启动子。E2 抑制癌基因表达的机制以及 E2 介导这种沉默的细胞因子在很大程度上尚不清楚。我们进行了一项无偏见的、全基因组 siRNA 筛选和一系列次级筛选，鉴定出 96 个有助于 HPV LCR 抑制的细胞基因。除了证实 E2 结合溴结构域蛋白 Brd4 在 E2 介导的沉默中的作用外，我们还鉴定了一些以前未涉及 E2 抑制的基因，包括去甲基化酶 JARID1C/SMCX 以及 NuA4/TIP60 组蛋白乙酰转移酶复合物的组成部分 EP400。这些基因中的每一个都独立地和累加地促进 E2 介导的沉默，表明 E2 通过几种不同的细胞复合物起作用以抑制 E6 和 E7 的表达。
