@article{0efec85b8115407aa20b9dfa05a91248,
title = "Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound",
abstract = "DNA-reactive compounds are harnessed for cancer chemotherapy. Their genotoxic effects are considered to be the main mechanism for the cytotoxicity to date. Because this mechanism preferentially affects actively proliferating cells, it is postulated that the cytotoxicity is specific to cancer cells. Nonetheless, they do harm normal quiescent cells, suggesting that there are other cytotoxic mechanisms to be uncovered. By employing doxorubicin as a representative DNA-reactive compound, we have discovered a cytotoxic mechanism that involves a cellular noncoding RNA (ncRNA) nc886 and protein kinase R (PKR) that is a proapoptotic protein. nc886 is transcribed by RNA polymerase III (Pol III), binds to PKR, and prevents it from aberrant activation in most normal cells. We have shown here that doxorubicin evicts Pol III from DNA and, thereby, shuts down nc886 transcription. Consequently, the instantaneous depletion of nc886 provokes PKR and leads to apoptosis. In a short-pulse treatment of doxorubicin, these events are the main cause of cytotoxicity preceding the DNA damage response in a 3D culture system as well as the monolayer cultures. By identifying nc886 as a molecular signal for PKR to sense doxorubicin, we have provided an explanation for the conundrum why DNA-damaging drugs can be cytotoxic to quiescent cells that have the competent nc886/PKR pathway.",
keywords = "Cytotoxicity, Doxorubicin, Nc886, Protein kinase R, RNA polymerase III",
author = "Nawapol Kunkeaw and Lee, {Yeon Su} and Im, {Wonkyun Ronny} and Jang, {Jiyoung Joan} and Song, {Min Ji} and Bobae Yang and Park, {Jong Lyul} and Kim, {Seon Young} and Yongsuk Ku and Yoosik Kim and Sangmin Kang and Jo, {Hye Ram} and Jeong, {Jae Hoon} and Lee, {Hyun Sung} and Lee, {Ju Seog} and Kim, {Hyoung Pyo} and Johnson, {Betty H.} and Kim, {In Hoo} and Lee, {Yong Sun}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Drs. Anindya Dutta and Etsuko Shibata (University of Virginia) for helpful discussion and Drs. Glauco R. Souza and Kim Brath (n3D Biosciences and Greiner Bio-One) and Ms. Lauren S. Richardson for assistance with the 3D culture. This work was supported by National Cancer Center, Korea Grants NCC-1810071-1 (to Y.S.L.) and NCC-1810072-1 (to I.-H.K.), the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation funded by Ministry of Science and ICT Grant NRF-2017M3C9A6044517 (to Y.-S.L.), and Thailand Research Fund Grant MRG5980034 (to N.K.). Funding Information: We thank Drs. Anindya Dutta and Etsuko Shibata (University of Virginia) for helpful discussion and Drs. Glauco R. Souza and Kim Brath (n3D Biosciences and Greiner Bio-One) and Ms. Lauren S. Richardson for assistance with the 3D culture. This work was supported by National Cancer Center, Korea Grants NCC-1810071-1 (to Y.S.L.) and NCC-1810072-1 (to I.-H.K.), the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation funded by Ministry of Science and ICT Grant NRF-2017M3C9A6044517 (to Y.-S.L.), and Thailand Research Fund Grant MRG5980034 (to N.K.). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
doi = "10.1073/pnas.1814510116",
language = "English (US)",
volume = "116",
pages = "8289--8294",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "17",
}