The journey of RNA polymerase II (Pol II) as it transcribes a gene is anything but a smooth ride. Transcript elongation is discontinuous and can be perturbed by intrinsic regulatory barriers, such as promoter-proximal pausing, nucleosomes, RNA secondary structures and the underlying DNA sequence. More substantial blocking of Pol II translocation can be caused by other physiological circumstances and extrinsic obstacles, including other transcribing polymerases, the replication machinery and several types of DNA damage, such as bulky lesions and DNA double-strand breaks. Although numerous different obstacles cause Pol II stalling or arrest, the cell somehow distinguishes between them and invokes different mechanisms to resolve each roadblock. Resolution of Pol II blocking can be as straightforward as temporary backtracking and transcription elongation factor S-II (TFIIS)-dependent RNA cleavage, or as drastic as premature transcription termination or degradation of polyubiquitylated Pol II and its associated nascent RNA. In this Review, we discuss the current knowledge of how these different Pol II stalling contexts are distinguished by the cell, how they overlap with each other, how they are resolved and how, when unresolved, they can cause genome instability.

RNA 聚合酶 II (Pol II) 转录基因的旅程绝非一帆风顺。转录本延伸是不连续的，可能受到内在调节障碍的干扰，例如启动子近端暂停、核小体、RNA 二级结构和底层 DNA 序列。其他生理环境和外在障碍可能会导致更严重的 Pol II 易位阻断，包括其他转录聚合酶、复制机制和几种类型的 DNA 损伤，例如大体积损伤和 DNA 双链断裂。尽管许多不同的障碍导致 Pol II 停滞或停滞，但细胞以某种方式区分它们并调用不同的机制来解决每个障碍。 Pol II 阻断的解决可以像临时回溯和转录延伸因子 S-II (TFIIS) 依赖性 RNA 切割一样简单，也可以像多泛素化 Pol II 及其相关新生 RNA 的过早转录终止或降解一样剧烈。在这篇综述中，我们讨论了当前的知识：细胞如何区分这些不同的 Pol II 停滞环境、它们如何相互重叠、如何解决它们以及在未解决时它们如何导致基因组不稳定。