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Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound

Authors
 Nawapol Kunkeaw  ;  Yeon-Su Lee  ;  Wonkyun Ronny Im  ;  Jiyoung Joan Jang  ;  Min-Ji Song  ;  Bobae Yang  ;  Jong-Lyul Park  ;  Seon-Young Kim  ;  Yongsuk Ku  ;  Yoosik Kim  ;  Sangmin Kang  ;  Hye-ram Jo  ;  Jae-Hoon Jeong  ;  Hyun-Sung Lee  ;  Ju-Seog Lee  ;  Hyoung-Pyo Kim  ;  Betty H. Johnson  ;  In-Hoo Kim  ;  Yong Sun Lee 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.116(17) : 8289-8294, 2019 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2019
Keywords
RNA polymerase III ; cytotoxicity ; doxorubicin ; nc886 ; protein kinase R
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.
Files in This Item:
T201905839.pdf Download
DOI
10.1073/pnas.1814510116
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Environmental Medical Biology (환경의생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hyoung Pyo(김형표) ORCID logo https://orcid.org/0000-0003-1441-8822
Song, Min Ji(송민지)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175217
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