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Title 

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

Authors 

N KunkeawY S LeeW R ImJ J JangM J SongB YangJong Lyul ParkSeon-Young KimY KuY KimS KangH R JoJ H JeongH S LeeJ S LeeH P KimB H JohnsonI H Kim

Publisher 

National Academy of Sciences

Issue Date 

2019

Citation 

Proceedings of the National Academy of Sciences of the United States of America

Keywords 

nc886protein kinase RdoxorubicincytotoxicityRNA polymerase III

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.

URI 

https://doi.org/10.1073/pnas.1814510116/-/DCSupplemental

ISSN 

0027-8424

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-07-10


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