Shin, Seung HoLee, Ji SuZhang, Jia-MinChoi, SungbinBoskovic, Zarko V.Zhao, RanSong, MengqiuWang, RuiTian, JieLee, Mee-HyunKim, Jae HwanJeong, MinjuLee, Jung HyunPetukhov, MichaelLee, Sam W.Kim, Sang GyunZou, LeeByun, Sanguine2020-11-112020-11-112020-07-31Shin, S. H., Lee, J. S., Zhang, J. M., Choi, S., Boskovic, Z. V., Zhao, R., Song, M., Wang, R., Tian, J., Lee, M. H., Kim, J. H., Jeong, M., Lee, J. H., Petukhov, M., Lee, S. W., Kim, S. G., Zou, L., & Byun, S. (2020). Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells. Science advances, 6(31), eaay9131. https://doi.org/10.1126/sciadv.aay9131https://hdl.handle.net/1808/30828This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.http://creativecommons.org/licenses/by-nc/4.0/Article10.1126/sciadv.aay9131https://orcid.org/0000-0002-2694-3889https://orcid.org/0000-0002-3569-217Xhttps://orcid.org/0000-0001-5919-002Xhttps://orcid.org/0000-0002-2472-6944https://orcid.org/0000-0001-9376-527Xhttps://orcid.org/0000-0003-1249-9876https://orcid.org/0000-0001-9775-165Xhttps://orcid.org/0000-0003-0777-102Xhttps://orcid.org/0000-0003-3771-1343https://orcid.org/0000-0002-4114-7338https://orcid.org/0000-0001-9548-2425https://orcid.org/0000-0003-3094-1058https://orcid.org/0000-0003-3903-5887PMC7399646openAccess