TEAD is required for DNA repair independent of its transcriptional function

Abstract The TEA domain family members 1-4 (TEADs) are major transcription factors for YAP/TAZ transcription activators in the Hippo pathway, regulating many biological processes, including development, tissue homeostasis, and tumorigenesis through target genes. Their amplification/upregulation correlates with poor prognosis in cancer patients. Although the Hippo pathway continues to be elucidated, it is clear that TEAD largely exerts its actions via transcriptional regulation. Here, we uncover an unexpected role for TEADs in the DNA damage response. Using comparative mass spectrometry, we demonstrate that TEADs interact with several DNA repair proteins. We further show that TEADs form DNA damage-induced nuclear foci that co-localize with DNA damage markers, γH2AX, and RIF1. We also found that TEADs are required for resistance to DNA damage, maintaining genome stability, and resolution of double strand break repair that is independent from the Hippo pathway and its transcriptional role. Our results establish a new role for TEADs in DNA repair and therefore, highlight a critical consideration in therapeutically targeting the Hippo pathway.