Global unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate

Complex molecular responses preserve gene expression accuracy and genome integrity in the face of environmental perturbations. Here we report that, in response to UV-irradiation, RNA Polymerase II (RNAPII) molecules are dynamically and synchronously released from promoter-proximal regions to promote uniform and accelerated scanning of the whole transcribed genome. The maximised influx of de novo released RNAPII correlates with increased sensing of damaged sites, as confirmed by RNAPII accumulation at dipyrimidine sites and by the average slow-down of elongation rates in gene bodies. By triggering this transcription elongation ‘safe’ mode, endangered cells guarantee an efficient DNA repair regardless of damage location, gene size and transcription level. Accordingly, in clinically-relevant samples we detect low and homogenous rates of mutational signatures associated with UV-irradiation or cigarette-smoke across all active genes. Together, our data highlight a novel functional advantage associated with regulation of promoter-proximal pausing and provide unanticipated insights into the mechanism underlying the central role of active transcription in shaping the mutagenic landscape of cancer genomes.

当面临环境扰动时，复杂的分子应答机制可维持基因表达的准确性与基因组的完整性。本研究发现，在紫外线（UV）照射刺激下，RNA聚合酶II（RNA Polymerase II，RNAPII）分子会从启动子近端区域被动态且同步地释放，以此促进对整个转录基因组的均匀且加速的扫描过程。从头释放的RNA聚合酶II的最大流入通量，与受损位点的感知效率提升呈正相关，这一点可通过RNA聚合酶II在二嘧啶位点的聚集，以及基因本体中延伸速率的平均放缓得到证实。通过激活这一转录延伸‘安全模式’，受损伤威胁的细胞可确保高效的DNA修复，且不受损伤位置、基因大小及转录水平的影响。因此，在临床相关样本中，我们在所有活跃基因中均检测到与紫外线照射或吸烟相关的突变特征，其发生率较低且分布均匀。综上，本研究数据揭示了启动子近端暂停调控相关的全新功能优势，并为解析活跃转录在塑造癌症基因组诱变景观中核心作用的潜在机制提供了意想不到的新视角。