Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells

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Issue Date
2020-07-31Author
Shin, Seung Ho
Lee, Ji Su
Zhang, Jia-Min
Choi, Sungbin
Boskovic, Zarko V.
Zhao, Ran
Song, Mengqiu
Wang, Rui
Tian, Jie
Lee, Mee-Hyun
Kim, Jae Hwan
Jeong, Minju
Lee, Jung Hyun
Petukhov, Michael
Lee, Sam W.
Kim, Sang Gyun
Zou, Lee
Byun, Sanguine
Publisher
American Association for the Advancement of Science
Type
Article
Article Version
Scholarly/refereed, publisher version
Rights
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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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.
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
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Citation
Shin, 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.aay9131
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