文章：

靶向癌症的转录周期

Targeting transcription cycles in cancer

原文发布日期：2021-10-21

DOI: 10.1038/s41568-021-00411-8

类型: Review Article

开放获取: 否

英文摘要：

Accurate control of gene expression is essential for normal development and dysregulation of transcription underpins cancer onset and progression. Similar to cell cycle regulation, RNA polymerase II-driven transcription can be considered as a unidirectional multistep cycle, with thousands of unique transcription cycles occurring in concert within each cell. Each transcription cycle comprises recruitment, initiation, pausing, elongation, termination and recycling stages that are tightly controlled by the coordinated action of transcriptional cyclin-dependent kinases and their cognate cyclins as well as the opposing activity of transcriptional phosphatases. Oncogenic dysregulation of transcription can entail defective control of gene expression, either at select loci or more globally, impacting a large proportion of the genome. The resultant dependency on the core-transcriptional machinery is believed to render ‘transcriptionally addicted’ cancers sensitive to perturbation of transcription. Based on these findings, small molecules targeting transcriptional cyclin-dependent kinases and associated proteins hold promise for the treatment of cancer. Here, we utilize the transcription cycles concept to explain how dysregulation of these finely tuned gene expression processes may drive tumorigenesis and how therapeutically beneficial responses may arise from global or selective transcriptional perturbation. This conceptual framework helps to explain tumour-selective transcriptional dependencies and facilitates the rational design of combination therapies.

摘要翻译： 

基因表达的精准调控对正常发育至关重要，转录失调则是癌症发生与进展的基础。与细胞周期调控类似，RNA聚合酶II驱动的转录可被视为单向多步骤循环，每个细胞内有数千个独特转录循环协同进行。每个转录循环包含招募、起始、暂停、延伸、终止和回收阶段，这些阶段受到转录性细胞周期蛋白依赖性激酶及其对应细胞周期蛋白的协同作用，以及转录性磷酸酶的对抗性活动的严格调控。致癌性转录失调可能导致基因表达控制缺陷，这种缺陷可能发生在特定基因位点，也可能更广泛地影响大部分基因组。这种对核心转录机制产生的依赖性，使得"转录成瘾"的癌症对转录扰动具有敏感性。基于这些发现，靶向转录性细胞周期蛋白依赖性激酶及相关蛋白的小分子药物为癌症治疗带来了希望。本文运用转录循环概念阐释这些精密调控的基因表达过程如何驱动肿瘤发生，以及全局性或选择性转录扰动如何产生治疗益处。这一理论框架有助于解释肿瘤选择性转录依赖性，并促进联合疗法的合理设计。

原文链接：

Targeting transcription cycles in cancer