Antisense Transcription in Gammaretroviruses as a Mechanism of Insertional Activation of Host Genes
Antisense Transcription in Gammaretroviruses as a Mechanism of Insertional Activation of Host Genes
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DOI：
10.1128/jvi.02088-09
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发表时间：
2010-02
影响因子：
5.4
通讯作者：
M. Rasmussen;B. Ballarín-González;Jinghua Liu;L. B. Lassen;A. Füchtbauer;E. Füchtbauer;A. Nielsen;F. Pedersen
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文献类型：
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作者：
M. Rasmussen;B. Ballarín-González;Jinghua Liu;L. B. Lassen;A. Füchtbauer;E. Füchtbauer;A. Nielsen;F. Pedersen
逆转录病毒的转录始于整合原病毒的U3-R区边界，并继续单向地产生正极性的基因组和mRNA产物。最近的几项研究表明，在复杂的逆转录病毒中存在天然存在的负极性蛋白质编码转录本。我们在此报告了在简单小鼠白血病病毒（MLV）负极性转录物的鉴定。在SL3-3和Akv MLV诱导的t细胞和b细胞淋巴瘤中，反义转录本在前病毒5 '长末端重复序列（LTR）的U3区启动，并继续进入细胞原癌基因Jdp2和Bach2，形成由病毒和宿主序列组成的嵌合转录本。这一现象在体内得到了验证，使用敲入小鼠模型，在已知激活b细胞淋巴瘤中Nras的位置上有单个LTR纯合。cDNA末端5 ‘快速扩增（RACE）分析表明，在5 ’ LTR的U3区存在广泛的起始位点，我们的数据首次显示了简单逆转录病毒的负极性转录活性在U3区起始，并提示了一种插入激活宿主基因的新机制。阐明5 ' LTR反义转录的性质和潜在的调控作用将与治疗载体的设计相关，并可能有助于提高对普遍存在的真核转录的认识。
ABSTRACT Transcription of retroviruses is initiated at the U3-R region boundary in the integrated provirus and continues unidirectionally to produce genomic and mRNA products of positive polarity. Several studies have recently demonstrated the existence of naturally occurring protein-encoding transcripts of negative polarity in complex retroviruses. We report here on the identification of transcripts of negative polarity in simple murine leukemia virus (MLV). In T-cell and B-cell lymphomas induced by SL3-3 and Akv MLV, antisense transcripts initiated in the U3 region of the proviral 5′ long terminal repeat (LTR) and continued into the cellular proto-oncogenes Jdp2 and Bach2 to create chimeric transcripts consisting of viral and host sequence. The phenomenon was validated in vivo using a knock-in mouse model homozygous for a single LTR at a position known to activate Nras in B-cell lymphomas. A 5′ rapid amplification of cDNA ends (RACE) analysis indicated a broad spectrum of initiation sites within the U3 region of the 5′ LTR. Our data show for the first time transcriptional activity of negative polarity initiating in the U3 region of simple retroviruses and suggest a novel mechanism of insertional activation of host genes. Elucidation of the nature and potential regulatory role of 5′ LTR antisense transcription will be relevant to the design of therapeutic vectors and may contribute to the increasing recognition of pervasive eukaryotic transcription.