尽管 DNA 损伤反应 (DDR) 途径具有深度保守性，但不同环境下的细胞对 DNA 损伤的易感性以及因基因组损伤而发生细胞凋亡的倾向却存在很大差异。与调节 DDR 相关的细胞信号传导途径之一是高度保守的 Wnt 途径，已知该途径可促进多种人类癌症对电离辐射引起的 DNA 损伤的抵抗力。然而，Wnt 信号转导与 DDR 的联系机制仍不清楚。在这里，我们使用果蝇的基因编码系统在体内可靠地诱导一致水平的 DNA 损伤，并证明翼成虫盘中的经典 Wnt 信号传导可以缓冲细胞在 DNA 双链断裂时防止细胞凋亡。我们发现，Wg（果蝇中的主要 Wnt 配体）通过配体加工蛋白酶 Rhomboid 激活表皮生长因子受体 (EGFR) 信号传导，进而以 Chk2、p53 和 E2F1 依赖性方式调节 DDR 。这些研究为高度增殖组织体内 Wnt 和 EGFR 通路对 DDR 的调节提供了机制上的见解。此外，它们还揭示了 Wnt 信号传导的生长和模式功能如何与促存活、抗凋亡活性相结合，从而促进面对基因组损伤时的发育鲁棒性。版权所有：© 2024 Ewen-Campen，Perrimon。这是一篇根据知识共享署名许可条款分发的开放获取文章，允许在任何媒体上不受限制地使用、分发和复制，前提是注明原始作者和来源。

Despite the deep conservation of the DNA damage response (DDR) pathway, cells in different contexts vary widely in their susceptibility to DNA damage and their propensity to undergo apoptosis as a result of genomic lesions. One of the cell signaling pathways implicated in modulating the DDR is the highly conserved Wnt pathway, which is known to promote resistance to DNA damage caused by ionizing radiation in a variety of human cancers. However, the mechanisms linking Wnt signal transduction to the DDR remain unclear. Here, we use a genetically encoded system in Drosophila to reliably induce consistent levels of DNA damage in vivo, and demonstrate that canonical Wnt signaling in the wing imaginal disc buffers cells against apoptosis in the face of DNA double-strand breaks. We show that Wg, the primary Wnt ligand in Drosophila, activates epidermal growth factor receptor (EGFR) signaling via the ligand-processing protease Rhomboid, which, in turn, modulates the DDR in a Chk2-, p53-, and E2F1-dependent manner. These studies provide mechanistic insight into the modulation of the DDR by the Wnt and EGFR pathways in vivo in a highly proliferative tissue. Furthermore, they reveal how the growth and patterning functions of Wnt signaling are coupled with prosurvival, antiapoptotic activities, thereby facilitating developmental robustness in the face of genomic damage.Copyright: © 2024 Ewen-Campen, Perrimon. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.