基因组中的富G重复序列可以形成独特的G-四链体（G4）二级结构，在基因的复制﹑转录等中发挥重要调控作用，已被确定是一个有效的疾病治疗靶点。小儿低级别胶质瘤（pLGG）是儿童中多发的严重肿瘤，目前还缺乏有效的疗手段。研究证实，原癌基因c-myb的扩增，特别是与QKI基因的重排在pLGG中常见，被认为是其特有的致病驱动因素。我们研究证实，c-myb基因的启动子区可以形成G4结构，选择性稳定这种结构可以抑制启动子的活性，降低转录和蛋白表达，抑制肿瘤细胞增殖，可能是一个特异性的pLGG靶向治疗策略。本课题将进一步借助CD,FRET,NMR及DMS印迹等手段表征此G4结构的稳定性及作用模式，同时利用ChIP-seq﹑EMSA﹑荧光素酶等研究G4形成对转录的调控。最后利用小儿胶质瘤模型探讨G4稳定策略对pLGG放化疗敏感性的影响。本课题为开发新颖的pLGG精准靶向治疗策略提供了新思路。

The c-myb promoter contains multiple GGA repeats beginning 17 bp downstream of the transcription initiation site. GGA repeats have been previously shown to form unusual DNA structures in solution. Results from chemical footprinting, circular dichroism and RNA and DNA polymerase arrest assays on oligonucleotides representing the GGA repeat region of the c-myb promoter demonstrate that the element is able to form tetrad: heptad: heptad: tetrad (T:H:H:T) G-quadruplex structures by stacking two tetrad:heptad G-quadruplexes formed by two of the three (GGA)4 repeats. Deletion of one or two (GGA)4 motifs destabilizes this secondary structure and.increases c-myb promoter activity, indicating that the G-quadruplexes formed in the c-myb GGA repeat region may act as a negative regulator of the c-myb promoter. Complete deletion of the c-myb GGA repeat region abolishes c-myb promoter activity, indicating dual roles of the c-myb GGA repeat element as both a transcriptional repressor and an activator. Our findings show that the T:H:H:T G-quadruplex-forming region in the c-myb promoter is a critical cis-acting element and may repress c-myb promoter activity .