Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Nat Commun. 2022 Jun 24;13(1):3624. doi: 10.1038/s41467-022-31329-w.
The precise regulation of RNA Polymerase II (Pol II) transcription after genotoxic stress is crucial for proper execution of the DNA damage-induced stress response. While stalling of Pol II on transcription-blocking lesions (TBLs) blocks transcript elongation and initiates DNA repair in cis, TBLs additionally elicit a response in trans that regulates transcription genome-wide. Here we uncover that, after an initial elongation block in cis, TBLs trigger the genome-wide VCP-mediated proteasomal degradation of promoter-bound, P-Ser5-modified Pol II in trans. This degradation is mechanistically distinct from processing of TBL-stalled Pol II, is signaled via GSK3, and contributes to the TBL-induced transcription block, even in transcription-coupled repair-deficient cells. Thus, our data reveal the targeted degradation of promoter-bound Pol II as a critical pathway that allows cells to cope with DNA damage-induced transcription stress and enables the genome-wide adaptation of transcription to genotoxic stress.
在基因毒性应激后，RNA 聚合酶 II（Pol II）转录的精确调控对于适当执行 DNA 损伤诱导的应激反应至关重要。虽然 Pol II 在转录阻断损伤（TBL）上的停滞阻止了转录延伸并在顺式中启动了 DNA 修复，但 TBL 还会引发跨式反应，从而调节全基因组的转录。在这里，我们发现，在顺式中最初的延伸阻断之后，TBL 会触发全基因组范围内 VCP 介导的、与启动子结合的、P-Ser5 修饰的 Pol II 的蛋白酶体降解。这种降解在机制上与 TBL 停滞的 Pol II 的加工不同，通过 GSK3 发出信号，并有助于 TBL 诱导的转录阻断，即使在转录偶联修复缺陷的细胞中也是如此。因此，我们的数据揭示了启动子结合的 Pol II 的靶向降解是一种关键途径，使细胞能够应对 DNA 损伤诱导的转录应激，并使转录对基因毒性应激的全基因组适应成为可能。
