Defective double-strand break (DSB) repair leads to genomic instabilities that may augment carcinogenesis. DSBs trigger transient transcriptional silencing in the vicinity of transcriptionally active genes through multilayered processes instigated by Ataxia telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and poly-(ADP-ribose) polymerase 1 (PARP1). Novel factors have been identified that ensure DSB-induced silencing via two distinct pathways: direct inhibition of RNA Polymerase II (Pol II) mediated by negative elongation factor (NELF), and histone code editing by CDYL1 and histone deacetylases (HDACs) that catalyze H3K27me3 and erase lysine crotonylation, respectively. Here, we highlight major advances in understanding the mechanisms underlying transcriptional silencing at DSBs, and discuss its functional implications on repair. Furthermore, we discuss consequential links between DSB-silencing factors and carcinogenesis and discuss the potential of exploiting them for targeted cancer therapy.

有缺陷的双链断裂（DSB）修复导致基因组不稳定，可能会增加致癌作用。DSB通过由共济失调毛细血管扩张症（ATM），DNA依赖性蛋白激酶（DNA-PK）和聚（ADP-核糖）聚合酶1（PARP1）引发的多层过程触发转录活性基因附近的瞬时转录沉默。已发现确保通过两种不同途径确保DSB诱导沉默的新因素：直接抑制负伸长因子（NELF）介导的RNA聚合酶II（Pol II），以及CDYL1和催化H3K27me3的组蛋白脱乙酰基酶（HDAC）的组蛋白代码编辑和分别消除赖氨酸巴豆酰化。在这里，我们重点介绍了理解DSB转录沉默机制的主要进展，并讨论了其对修复的功能意义。