Institute of Toxicology, University Medical Center, Johannes Gutenberg University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Nucleic Acids Res. 2020 Dec 2;48(21):12085-12101. doi: 10.1093/nar/gkaa965.
Transcriptional regulation of DNA repair is of outmost importance for the restoration of DNA integrity upon genotoxic stress. Here we report that the potent environmental carcinogen benzo[a]pyrene (B[a]P) activates a cellular DNA damage response resulting in transcriptional repression of mismatch repair (MMR) genes (MSH2, MSH6, EXO1) and of RAD51, the central homologous recombination repair (HR) component, ultimately leading to downregulation of MMR and HR. B[a]P-induced gene repression is caused by abrogated E2F1 signalling. This occurs through proteasomal degradation of E2F1 in G2-arrested cells and downregulation of E2F1 mRNA expression in G1-arrested cells. Repression of E2F1-mediated transcription and silencing of repair genes is further mediated by the p21-dependent E2F4/DREAM complex. Notably, repression of DNA repair is also observed following exposure to the active B[a]P metabolite BPDE and upon ionizing radiation and occurs in response to a p53/p21-triggered, irreversible cell cycle arrest marking the onset of cellular senescence. Overall, our results suggest that repression of MMR and HR is an early event during genotoxic-stress induced senescence. We propose that persistent downregulation of DNA repair might play a role in the maintenance of the senescence phenotype, which is associated with an accumulation of unrepairable DNA lesions.
转录调控在 DNA 修复中起着至关重要的作用，对于遗传毒性应激后 DNA 完整性的恢复至关重要。在这里，我们报告说，强效环境致癌物苯并[a]芘（B[a]P）激活了细胞 DNA 损伤反应，导致错配修复（MMR）基因（MSH2、MSH6、EXO1）和同源重组修复（HR）核心成分 RAD51 的转录抑制，最终导致 MMR 和 HR 的下调。B[a]P 诱导的基因抑制是由于 E2F1 信号的中断引起的。这是通过在 G2 期细胞中通过蛋白酶体降解 E2F1 和在 G1 期细胞中下调 E2F1 mRNA 表达来实现的。E2F1 介导的转录抑制和修复基因的沉默进一步由 p21 依赖性 E2F4/DREAM 复合物介导。值得注意的是，在暴露于活性 B[a]P 代谢物 BPDE 以及电离辐射后，也观察到 DNA 修复的抑制，并且发生在 p53/p21 触发的不可逆细胞周期阻滞之后，标志着细胞衰老的开始。总体而言，我们的研究结果表明，MMR 和 HR 的抑制是遗传毒性应激诱导衰老过程中的早期事件。我们提出，DNA 修复的持续下调可能在衰老表型的维持中发挥作用，这与无法修复的 DNA 损伤的积累有关。
