Gertzmann Dörthe, Presek Cornelius, Mattes Anna Lena, Sänger Marco, Zoller Marie, Schülein-Völk Christina, Ade Carsten P, Eilers Martin, Gaubatz Stefan
Department of Biochemistry and Cell Biology, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
Core Unit High-Content Microscopy, Theodor Boveri Institute, Biocenter, Julius Maximilian University Würzburg, Am Hubland, 97074, Würzburg, Germany.
EMBO Rep. 2025 Aug;26(16):4017-4039. doi: 10.1038/s44319-025-00514-5. Epub 2025 Jul 4.
Replication stress is a driver of genomic instability, contributing to carcinogenesis by causing DNA damage and mutations. While YAP, the downstream co-activator of the Hippo signaling pathway, plays a crucial role in regulating cell growth and differentiation, it is unclear whether it generates replication stress exploitable for therapy. Here, we report that oncogenic YAP shortens the G1 phase through increased CDK4/6 activity, leading to early S-phase entry. This causes origin underlicensing, an overall reduced rate of DNA replication, and, unusually, an accelerated speed of individual replication forks. CHK1 inhibition in cells expressing oncogenic YAP results in DNA damage during S-phase, which is not due to premature CDK1 activation or mitotic entry. Sensitivity to CHK1 inhibition depends on the YAP-TEAD interaction and involves a global increase in transcription and an increase in transcription-replication conflicts (TRCs). Replication stress from oncogenic YAP can be mitigated by restoring G1 length through partial CDK4/6 inhibition or by reducing YAP-induced hypertranscription. Our findings suggest a potential therapeutic strategy for targeting YAP-dependent cancers by exploiting their vulnerability to replication stress.
复制应激是基因组不稳定的驱动因素，通过导致DNA损伤和突变促进癌症发生。虽然Hippo信号通路的下游共激活因子YAP在调节细胞生长和分化中起关键作用，但尚不清楚它是否会产生可用于治疗的复制应激。在此，我们报告致癌性YAP通过增加CDK4/6活性缩短G1期，导致早期进入S期。这会导致起始位点许可不足、DNA复制总体速率降低，并且异常的是，单个复制叉的速度加快。在表达致癌性YAP的细胞中抑制CHK1会导致S期DNA损伤，这不是由于CDK1过早激活或进入有丝分裂所致。对CHK1抑制的敏感性取决于YAP-TEAD相互作用，涉及转录的整体增加和转录-复制冲突（TRC）的增加。致癌性YAP引起的复制应激可通过部分抑制CDK4/6恢复G1期长度或减少YAP诱导的过度转录来减轻。我们的研究结果提示了一种潜在的治疗策略，即通过利用YAP依赖性癌症对复制应激的易感性来靶向治疗此类癌症。
