Inhibition of transcription caused by DNA damage-impaired RNA polymerase II (Pol II) elongation conceals a local increase in de novo transcription, slowly progressing from Transcription Start Sites (TSSs) to gene ends. Although associated with accelerated repair of Pol II-encountered lesions and limited mutagenesis, it is still unclear how this mechanism is maintained during genotoxic stress-recovery. Here we uncover a widespread gain in chromatin accessibility and preservation of the active H3K27ac mark after UV-irradiation. The concomitant increase in Pol II escape from promoter-proximal pause (PPP) sites of most active genes, PROMPTs and enhancer RNAs favors unrestrained initiation, as evidenced by the synthesis of nascent RNAs including start RNAs. Accordingly, drug-inhibition of PPP-release replenishes levels of pre-initiating Pol II at TSSs after UV. Our data show that such continuous engagement of Pol II molecules ensures maximal transcription-driven repair throughout expressed genes and regulatory loci. Importantly, revealing this unanticipated regulatory layer of UV-response provides physiological relevant traction to the emerging concept that Pol II initiation rate is determined by pause-release dynamics.

中文翻译：

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连续转录起始可确保所有转录的基因和调节区的牢固修复。

由DNA损伤受损的RNA聚合酶II（Pol II）延长引起的转录抑制隐藏了从头转录的局部增加，从转录起始位点（TSS）缓慢发展到基因末端。尽管与Pol II引起的病变的加速修复和有限的诱变相关，但仍不清楚在遗传毒性应激恢复过程中如何维持这种机制。在这里，我们发现了染色质可及性的广泛提高以及紫外线照射后活性H3K27ac标记的保存。Pol II伴随着大多数活性基因，PROMPT和增强子RNA的启动子近暂停（PPP）位点逃逸的增加，有利于不受限制的起始，这是由新生RNA包括起始RNA的合成所证明的。因此，PPP释放的药物抑制作用可补充紫外线后TSS的启动前Pol II的水平。我们的数据表明，Pol II分子的这种连续参与可确保在整个表达的基因和调节基因座中实现最大的转录驱动修复。重要的是，揭示这一意外的紫外线响应调节层可为新兴的观念提供生理相关的牵引力，即Pol II的起始速率由暂停释放动力学决定。