识别与复制应激相关的基因是了解癌症进化和确定治疗靶点的关键。在这里，我们证明 CDK12 可以防止转录复制冲突 (TRC) 以及在 MYC 癌基因失调时激活细胞毒性复制应激。 CDK12 通过 PARP 依赖性 DDR 信号传导和具有延伸能力的 RNAPII 被招募到受损基因处，以抑制转录。 CDK12 的缺失或化学抑制会导致受损基因的 DDR 抗性转录。 CDK12的缺失加剧了MYC过表达细胞中的TRC，并导致双链DNA断裂的积累，发生在同向早期复制区域和转录基因之间。总体而言，我们的数据表明 CDK12 通过抑制受损基因的转录来保护基因组完整性，这是在癌基因诱导的 TRC 中正确解析 DSB 所必需的。这提供了一个基本原理，解释了 CDK12 缺乏如何在肿瘤进化过程中促进早期复制区域的串联复制，以及 CDK12 靶向如何加剧肿瘤中的复制应激。© 2024。作者。

The identification of genes involved in replicative stress is key to understanding cancer evolution and to identify therapeutic targets. Here, we show that CDK12 prevents transcription-replication conflicts (TRCs) and the activation of cytotoxic replicative stress upon deregulation of the MYC oncogene. CDK12 was recruited at damaged genes by PARP-dependent DDR-signaling and elongation-competent RNAPII, to repress transcription. Either loss or chemical inhibition of CDK12 led to DDR-resistant transcription of damaged genes. Loss of CDK12 exacerbated TRCs in MYC-overexpressing cells and led to the accumulation of double-strand DNA breaks, occurring between co-directional early-replicating regions and transcribed genes. Overall, our data demonstrate that CDK12 protects genome integrity by repressing transcription of damaged genes, which is required for proper resolution of DSBs at oncogene-induced TRCs. This provides a rationale that explains both how CDK12 deficiency can promote tandem duplications of early-replicated regions during tumor evolution, and how CDK12 targeting can exacerbate replicative-stress in tumors.© 2024. The Author(s).