The Sec6/8 (a.k.a. Exocyst) Complex Supports DNA Repair Fidelity

Date

2014-04-14

Authors

Torres, Michael Jason 1982-

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Abstract

The exocyst complex, first described in yeast, is a heterooctomeric complex that serves as a signaling platform to mediate cellular responses to diverse spatial and temporal cues. Evidence suggests that the exocyst might contribute to oncogenesis, potentially by disrupting spatial and temporal regulation of pathways critical to determining cell survival vs. apoptosis. Our work investigated how cancer cells subvert the exocyst to upregulate the AKT (v-akt murine thymoma viral oncogene) pro-survival pathway through the innate immune protein TBK1 (TANK-binding kinase 1). siRNA-mediated depletion of TBK1 in pancreatic and breast cancer cell lines results in apoptosis, which is mediated through the AKT pathway. Pharmacological inhibition of TBK1 recapitulates the apoptotic phenotype in mouse orthotopic models. Additionally, my work uncovered exocyst participation in the regulation of DNA repair. The isolation of multiple components of the DNA damage response (DDR) within the human exocyst protein-protein interaction network, together with the identification of Sec8 as a suppressor of the p53 response, prompted an investigation of functional interactions between the exocyst and the DDR. We found that exocyst perturbation resulted in a radioresistance phenotype to ionizing radiation (IR) that was associated with 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. Exocyst-dependent modulation of the DDR is, at least in part, through restraint of the associated chromatin modifiers ATF2 and RNF20. Exocyst perturbation resulted in aberrant accumulation of ATF2 and RNF20; the promiscuous accumulation of DDR-associated chromatin marks; and IR-induced increased Rad51 repairosomes. Thus, the exocyst indirectly supports DNA repair fidelity by limiting formation of repair chromatin in the absence of a DNA damage signal. This newly revealed regulation of DNA repair by the exocyst may provide additional insight into the emerging observations of DNA damage protein involvement in pathways not canonically associated DNA repair, such as the host cytokinesis, host defense response, and maintenance of cilia. This work further substantiates the importance of the exocyst in normal cell biology and gives insight into how disruption of exocyst function can result in disease.

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