从TOBP1中取代CIP2A的E2位移激活了在乳头瘤病毒生命周期期间的DNA损伤反应
bioRxiv : the preprint server for biology
|November 24, 2025
概括
乳头瘤病毒E2蛋白通过操纵细胞信号通路来激活DNA损伤反应 (DDR). 这种ATM驱动的DDR促进病毒复制和细胞增殖,为HPV相关癌症提供治疗点.
科学领域:
- 细胞生物学 细胞生物学
- 病毒学 病毒学
- 分子瘤学分子瘤学
背景情况:
- 乳头瘤病毒生命周期取决于上皮细胞的分化.
- 病毒操纵宿主细胞过程,包括DNA损伤反应 (DDR),进行复制.
- 了解病毒蛋白与宿主DDR机械的相互作用,对于治疗开发至关重要.
研究的目的:
- 阐明乳头瘤病毒E2蛋白激活DNA损伤反应 (DDR) 的机制.
- 研究E2介导的DDR激活在病毒复制和细胞增殖中的作用.
- 探索针对HPV相关疾病中E2激活的DDR途径的治疗潜力.
主要方法:
- 研究了E2蛋白与关键DDR调节者的相互作用,如TOPBP1,CIP2A,PP2A,ATM和SIRT1.
- 利用各种细胞培养系统,包括质细胞和表达E2.2的癌细胞系.
- 采用ATM抑制来评估其对E2表达细胞和瘤的影响.
主要成果:
- 乳头瘤病毒E2蛋白通过将CIP2A从TOPBP1取代,从而激活DDR,从而导致PP2A抑制和ATM酸化.
- E2与ATM和TOPBP1形成复合体,促进"ATM上升,ATR下降"状态,有利于病毒复制和细胞增殖.
- ATM抑制有选择性地杀死表达E2的细胞,包括在前瘤病变和HPV+口腔癌中的细胞.
结论:
- 乳头瘤病毒E2蛋白质劫持宿主DDR通路,特别激活ATM,同时抑制ATR,以促进病毒复制和细胞生长.
- 向ATM证明了早期HPV诱导的脑膜瘤和HPV阳性口腔癌的一个子集的有希望的治疗策略.
- 在HPV驱动的癌症中,E2-DDR相互作用代表了关键的脆弱性,这些癌症具有保留的E2表达和插曲性基因组.
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