Michael J. Torres, Raj K. Pandita, Ozlem Kulak, Rakesh Kumar, Etienne Formstecher, Nobuo Horikoshi, Kalpana Mujoo, Clayton R. Hunt, Yingming Zhao, Lawrence Lum, Aubhishek Zaman, Charles Yeaman, Michael A. White, Tej K. Pandita

The exocyst is a heterooctomeric complex well appreciated for its role in dynamic assembly of specialized membrane domains. Accumulating evidence indicates this macromolecular machine also serves as a physical platform that coordinates regulatory cascades supporting biological systems such as host defense signaling, cell fate, and energy homeostasis. The isolation of multiple components of the DNA damage response (DDR) as exocyst-interacting proteins, together with the identification of Sec8 as a suppressor of the p53 response, suggested functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in resistance to ionizing radiation (IR) and accelerated resolution of DNA damage. This occurred at the expense of genomic integrity, as enhanced recombination frequencies correlated with the accumulation of aberrant chromatid exchanges. Sec8 perturbation resulted in accumulation of ATF2 and RNF20, the promiscuous accumulation of DDR-associated chromatin marks, and Rad51 repairosomes. Thus, the exocyst supports DNA repair fidelity by limiting formation of repair chromatin in the absence of DNA damage.