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bioRxiv · 10.64898/2026.04.09.717588

Targeting Noncanonical TEAD Axis to Overcome DNA Repair-Driven Chemoresistance

Kim, D.-H.·Kim, J.·Kang, S.·Kim, H.-R.·Cho, S. C.·Kim, Y.·Roe, J.-S.·Shin, D.·No, K. T.·Park, H. W.
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Abstract

How transcription factors contribute to DNA damage repair (DDR) independent of canonical gene regulation remains poorly understood. Here, we show that DNA double-strand break (DSB) triggers a functional state transition in TEAD, disengaging it from YAP-dependent transcription and translocating it to DNA lesions as a chromatin-associated DDR factor. Upon genotoxic stress, TEAD is rapidly recruited to damaged chromatin through a biphasic mechanism involving early poly(ADP-ribose)-dependent recruitment followed by ATM-driven {gamma}H2AX-mediated retention. At DNA lesions, TEAD constrains chromatin over-relaxation, suppresses excessive end resection, and promotes non-homologous end joining (NHEJ) independent of its canonical function. Conserved residues within the TEA domain mediate this noncanonical chromatin engagement of TEAD and define a druggable N-terminal interface. Pharmacological targeting of this interface impaired TEAD-dependent DSB repair and sensitized tumors to chemotherapy. Together, these findings establish noncanonical TEAD as a critical DNA repair factor and a clinically actionable driver of chemoresistance, while providing a conceptual framework for understanding how broader families of transcription factors may be repurposed as targetable DNA damage regulators in cancer.

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Kim, D.-H., Kim, J., Kang, S., Kim, H.-R., Cho, S. C., Kim, Y., Roe, J.-S., Shin, D., No, K. T., Park, H. W.. 2026-04-13. Targeting Noncanonical TEAD Axis to Overcome DNA Repair-Driven Chemoresistance. https://doi.org/10.64898/2026.04.09.717588

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