文章：

超卷曲在MYC转录控制中的作用及其在分子治疗中的重要性

PThe role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics

原文发布日期：2009-11-12

DOI: 10.1038/nrc2733

类型: Review Article

开放获取: 否

要点：

1. MYC is a pivotal player in normal cells, not only in proliferation but also in apoptosis and differentiation. MYC is deregulated in most tumour types and stages.
2. MYC expression is sometimes an addictive character of cancer and is therefore an Achilles heel for cancer cells. Initial studies indicate that MYC suppression can lead to apoptosis and cell death in cancer cells, while producing only rapidly reversible effects in normal cells, providing a wide therapeutic window for specific and efficacious anti-tumour treatment.
3. Transcriptionally induced negative supercoiling is crucial for controlling MYC expression. The distance that this negative supercoiling travels upstream from the transcriptional start sites can be large (>1 kb) and is constrained within the boundaries imposed by looping and other features of the chromatin.
4. There are two important elements in the MYC promoter that are dynamically affected by negative supercoiling: far upstream element (FUSE) and NHE III₁.
5. FUSE, in concert with the effector proteins FUSE-binding protein (FBP), FBP-interacting repressor (FIR) and TFIIH, constitutes a cruise control system that can precisely control the rate of MYC promoter firing. NHE III₁ can exist in three different forms, of which two (duplex and single stranded) constitute an on switch and the third (G-quadruplex and i-motif) constitutes an off switch.
6. There are defined strategies to suppress MYC expression by small-molecule targeting of the FUSE–FBP interface or by small-molecule stabilization of the G-quadruplex or i-motif structure in the on–off switch.

要点翻译：

1. MYC是正常细胞中的关键调控因子，不仅参与增殖过程，还调控凋亡与分化。在大多数肿瘤类型及阶段中，MYC均存在失调现象。
2. MYC表达有时会成为癌症的成瘾性特征，因此也成为癌细胞的阿喀琉斯之踵。初步研究表明，抑制MYC可导致癌细胞凋亡和死亡，而对正常细胞仅产生快速可逆的影响，这为特异性高效抗肿瘤治疗提供了广阔的窗口期。
3. 转录诱导的负超螺旋对MYC表达调控至关重要。这种负超螺旋从转录起始位点向上游传递的距离可能很长（>1 kb），并受染色质环化及其他结构特征所形成的边界限制。
4. MYC启动子中存在两个受负超螺旋动态调控的重要元件：远端上游元件（FUSE）和核酸酶超敏元件III1（NHE III1）。
5. FUSE与其效应蛋白FUSE结合蛋白（FBP）、FBP相互作用阻遏蛋白（FIR）及TFIIH共同构成巡航控制系统，可精确调控MYC启动子的启动速率。NHE III1可存在三种不同形态，其中两种（双链和单链）构成启动开关，第三种（G-四链体和i-基序）构成关闭开关。
6. 目前已有明确策略可通过小分子靶向FUSE-FBP界面，或通过小分子稳定开关结构中G-四链体及i-基序结构来抑制MYC表达。

英文摘要：

MYC is deregulated in most tumour types, but an effective means to selectively target its aberrant expression is not yet available. Supercoiling that is induced by transcription has been demonstrated to have dynamic effects on DNA in the MYC promoter element: it converts duplex DNA to non-duplex DNA structures, even at considerable distances from the transcriptional start site. These non-duplex DNA structures, which control both turning on and off of transcription and the rate of transcription firing, are amenable to small-molecule targeting. This dynamic system provides a unique opportunity for the treatment of tumours in which MYC is an important oncogene.

摘要翻译： 

MYC在大多数肿瘤类型中均出现失调，但目前尚无有效手段选择性干预其异常表达。已有研究表明，转录诱导的超螺旋会对MYC启动子元件中的DNA产生动态影响：即使距转录起始位点相当远，它也能将双链DNA转化为非双链DNA结构。这些非双链DNA结构控制着转录的开启与关闭以及转录启动速率，并且可被小分子靶向。该动态系统为MYC作为重要癌基因的肿瘤治疗提供了独特契机。

原文链接：

The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics