Yes-associated protein (YAP) is a central player in cancer development, with functions extending beyond its recognized role in cell growth regulation. Recent work has identified a link between YAP/transcriptional coactivator with PDZ-binding motif (TAZ) and the DNA damage response. Here, we investigated the mechanistic underpinnings of the cross-talk between DNA damage repair and YAP activity. Ku70, a key component of the nonhomologous end joining pathway to repair DNA damage, engaged in a dynamic competition with TEAD4 for binding to YAP, limiting the transcriptional activity of YAP. Depletion of Ku70 enhanced interaction between YAP and TEAD4 and boosted YAP transcriptional capacity. Consequently, Ku70 loss enhanced tumorigenesis in colon cancer and hepatocellular carcinoma (HCC) in vivo. YAP impeded DNA damage repair and elevated genome instability by inducing PARP1 degradation through the SMURF2-mediated ubiquitin-proteasome pathway. Analysis of samples from patients with HCC substantiated the link between Ku70 expression, YAP activity, PARP1 levels, and genome instability. In conclusion, this research provides insight into the mechanistic interactions between YAP and key regulators of DNA damage repair, highlighting the role of a Ku70-YAP-PARP1 axis in preserving genome stability. Significance: Increased yes-associated protein transcriptional activity stimulated by loss of Ku70 induces PARP1 degradation by upregulating SMURF2 to inhibit DNA damage, driving genome instability and tumorigenesis.

中文翻译：

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Ku70 与 YAP 的结合改变了 PARP1 泛素化，以调节基因组稳定性和肿瘤发生。


Yes 相关蛋白 （YAP） 是癌症发展的核心参与者，其功能超出了其在细胞生长调节中公认的作用。最近的工作确定了 YAP/带有 PDZ 结合基序 （TAZ） 的转录共激活因子与 DNA 损伤反应之间的联系。在这里，我们研究了 DNA 损伤修复和 YAP 活性之间串扰的机制基础。Ku70 是修复 DNA 损伤的非同源末端连接途径的关键组分，与 TEAD4 进行动态竞争以结合 YAP，从而限制了 YAP 的转录活性。Ku70 的耗竭增强了 YAP 和 TEAD4 之间的相互作用，并提高了 YAP 转录能力。因此，Ku70 缺失在体内增强了结肠癌和肝细胞癌 （HCC） 的肿瘤发生。YAP 通过 SMURF2 介导的泛素-蛋白酶体途径诱导 PARP1 降解，从而阻碍 DNA 损伤修复和基因组不稳定性升高。对 HCC 患者样本的分析证实了 Ku70 表达、YAP 活性、PARP1 水平和基因组不稳定性之间的联系。总之，这项研究深入了解了 YAP 与 DNA 损伤修复的关键调节因子之间的机制相互作用，突出了 Ku70-YAP-PARP1 轴在保持基因组稳定性中的作用。意义： Ku70 缺失刺激的 yes 相关蛋白转录活性增加，通过上调 SMURF2 抑制 DNA 损伤来诱导 PARP1 降解，从而驱动基因组不稳定性和肿瘤发生。