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Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells
dc.contributor.author | Shin, Seung Ho | |
dc.contributor.author | Lee, Ji Su | |
dc.contributor.author | Zhang, Jia-Min | |
dc.contributor.author | Choi, Sungbin | |
dc.contributor.author | Boskovic, Zarko V. | |
dc.contributor.author | Zhao, Ran | |
dc.contributor.author | Song, Mengqiu | |
dc.contributor.author | Wang, Rui | |
dc.contributor.author | Tian, Jie | |
dc.contributor.author | Lee, Mee-Hyun | |
dc.contributor.author | Kim, Jae Hwan | |
dc.contributor.author | Jeong, Minju | |
dc.contributor.author | Lee, Jung Hyun | |
dc.contributor.author | Petukhov, Michael | |
dc.contributor.author | Lee, Sam W. | |
dc.contributor.author | Kim, Sang Gyun | |
dc.contributor.author | Zou, Lee | |
dc.contributor.author | Byun, Sanguine | |
dc.date.accessioned | 2020-11-11T14:52:42Z | |
dc.date.available | 2020-11-11T14:52:42Z | |
dc.date.issued | 2020-07-31 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30828 | |
dc.description | This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. | en_US |
dc.description.abstract | 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. | en_US |
dc.description.sponsorship | NIH 1RO1CA142805 | en_US |
dc.description.sponsorship | National Research Foundation of Korea (NRF) grant (NRF-2017R1C1B1006072) | en_US |
dc.publisher | American Association for the Advancement of Science | en_US |
dc.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. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | en_US |
dc.title | Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Boskovic, Zarko V. | |
kusw.kudepartment | Medicinal Chemistry | en_US |
dc.identifier.doi | 10.1126/sciadv.aay9131 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-2694-3889 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-3569-217X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-5919-002X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-2472-6944 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9376-527X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-1249-9876 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9775-165X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-0777-102X | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3771-1343 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-4114-7338 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-9548-2425 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3094-1058 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0003-3903-5887 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7399646 | en_US |
dc.rights.accessrights | openAccess | en_US |