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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA
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Recruitment of the de novo DNA methyltransferase Dnmt3a by Kaposi's sarcoma-associated herpesvirus LANA

机译：卡波西氏肉瘤相关疱疹病毒LANA募集从头DNA甲基转移酶Dnmt3a

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摘要

The Kaposi's sarcoma-associated herpesvirus LANA protein is expressed in all Kaposi's sarcoma-associated herpesvirus-infected cells, including the tumor cells of endemic and AIDS-associated Kaposi sarcoma, primary effusion lymphoma, and Castleman disease. LANA modulates cell gene expression, but the mechanisms of LANA-mediated transcriptional reprogramming are poorly understood. LANA-repressed cell genes were identified by using retro-viral-transduced telomerase-immortalized microvascular endothe-lial cells. Transciptional repression of targeted genes was relieved by treatment with the methyltransferase inhibitor 5-aza-2'-deoxy-cytidine, suggesting a role for DNA methylation in repression. We found that LANA coprecipitated with DNA methyltransferases (Dnmts) and recruited endogenous DNA methyltransferase activity from the cell extract. LANA preferentially relocalized Dnmt3a from the nuclear matrix into the chromatin fraction. Further, LANA associated with repressed cellular promoters, recruited Dnmt3a to DNA, and facilitated de novo promoter methylation of a down-regulated gene, cadherin 13 (H-cadherin). The data provide an example of promoter-specific epigenetic DNA modification through viral protein recruitment of de novo Dnmt activity.
机译：卡波西氏肉瘤相关的疱疹病毒LANA蛋白在所有卡波西氏肉瘤相关的疱疹病毒感染的细胞中表达，包括地方性和艾滋病相关的卡波西氏肉瘤的肿瘤细胞，原发渗出性淋巴瘤和Castleman病。 LANA调节细胞基因表达，但对LANA介导的转录重编程的机制了解甚少。通过使用逆转录病毒转导的端粒酶永生化微血管内皮细胞来鉴定LANA抑制的细胞基因。通过用甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷处理，可以缓解靶向基因的转录抑制，提示DNA甲基化在抑制中的作用。我们发现LANA与DNA甲基转移酶（Dnmts）共沉淀，并从细胞提取物中募集了内源性DNA甲基转移酶活性。 LANA优先将Dnmt3a从核基质重新定位到染色质部分。此外，LANA与抑制的细胞启动子相关，将Dnmt3a募集到DNA，并促进下调基因钙粘着蛋白13（H-钙粘着蛋白）的从头启动子甲基化。数据提供了通过从头开始Dnmt活性的病毒蛋白募集而对启动子特异性表观遗传DNA修饰的例子。

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