TEAD proteins associate with DNA repair proteins to facilitate cellular recovery from DNA damage.

Transcriptional enhanced associate domain family members 1-4 (TEADs) are a family of four transcription factors and the major transcriptional effectors of the Hippo pathway. In order to activate transcription, TEADs rely on interactions with other proteins, such as the transcriptional effectors YAP and TAZ. Nuclear protein interactions involving TEADs influence the transcriptional regulation of genes involved in cell growth, tissue homeostasis, and tumorigenesis. Clearly, protein interactions for TEADs are functionally important, but the full repertoire of TEAD interaction partners remains unknown. Here we employ an affinity purification mass spectrometry (AP-MS) approach to identify nuclear interacting partners of TEADs. We performed AP-MS experiment in parallel in two different cell types and compared a wildtype TEAD bait protein to an NLS mutant that does not localize to the nucleus. We quantified the results using SAINT analysis and found a significant enrichment of proteins linked to DNA damage including XRCC5, XRCC6, PARP1, and RIF1. In cellular assays, we found that TEADs co-localize with DNA damage-induced nuclear foci marked by γH2AX and RIF1. We also found that depletion of TEAD proteins makes cells more susceptible to DNA damage by various agents, and that depletion of TEADs promotes genomic instability. Additionally, depleting TEADs dampens the efficiency of DNA double-stranded break repair in reporter assays. Our results connect TEADs to DNA damage response processes, positioning DNA damage as an important avenue for further research of TEAD proteins.