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

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dc.contributor.authorKunkeaw, Nawapolko
dc.contributor.authorLee, Yeon-Suko
dc.contributor.authorIm, Wonkyun Ronnyko
dc.contributor.authorJang, Jiyoung Joanko
dc.contributor.authorSong, Min-Jiko
dc.contributor.authorYang, Bobaeko
dc.contributor.authorPark, Jong-Lyulko
dc.contributor.authorKim, Seon-Youngko
dc.contributor.authorKu, Yongsukko
dc.contributor.authorKim, Yoosikko
dc.contributor.authorKang, Sangminko
dc.contributor.authorJo, Hye-ramko
dc.contributor.authorJeong, Jae-Hoonko
dc.contributor.authorLee, Hyun-Sungko
dc.contributor.authorLee, Ju-Seogko
dc.contributor.authorKim, Hyoung-Pyoko
dc.contributor.authorJohnson, Betty H.ko
dc.contributor.authorKim, In-Hooko
dc.contributor.authorLee, Yong Sunko
dc.date.accessioned2019-05-10T04:30:02Z-
dc.date.available2019-05-10T04:30:02Z-
dc.date.created2019-05-10-
dc.date.created2019-05-10-
dc.date.created2019-05-10-
dc.date.issued2019-04-
dc.identifier.citationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.17, pp.8289 - 8294-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10203/261834-
dc.description.abstractDNA-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.-
dc.languageEnglish-
dc.publisherNATL ACAD SCIENCES-
dc.titleMechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound-
dc.typeArticle-
dc.identifier.wosid000465363700037-
dc.identifier.scopusid2-s2.0-85065163245-
dc.type.rimsART-
dc.citation.volume116-
dc.citation.issue17-
dc.citation.beginningpage8289-
dc.citation.endingpage8294-
dc.citation.publicationnamePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-
dc.identifier.doi10.1073/pnas.1814510116-
dc.contributor.localauthorKim, Yoosik-
dc.contributor.nonIdAuthorKunkeaw, Nawapol-
dc.contributor.nonIdAuthorLee, Yeon-Su-
dc.contributor.nonIdAuthorIm, Wonkyun Ronny-
dc.contributor.nonIdAuthorJang, Jiyoung Joan-
dc.contributor.nonIdAuthorSong, Min-Ji-
dc.contributor.nonIdAuthorYang, Bobae-
dc.contributor.nonIdAuthorPark, Jong-Lyul-
dc.contributor.nonIdAuthorKim, Seon-Young-
dc.contributor.nonIdAuthorKu, Yongsuk-
dc.contributor.nonIdAuthorKang, Sangmin-
dc.contributor.nonIdAuthorJo, Hye-ram-
dc.contributor.nonIdAuthorJeong, Jae-Hoon-
dc.contributor.nonIdAuthorLee, Hyun-Sung-
dc.contributor.nonIdAuthorLee, Ju-Seog-
dc.contributor.nonIdAuthorKim, Hyoung-Pyo-
dc.contributor.nonIdAuthorJohnson, Betty H.-
dc.contributor.nonIdAuthorKim, In-Hoo-
dc.contributor.nonIdAuthorLee, Yong Sun-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordAuthornc886-
dc.subject.keywordAuthorprotein kinase R-
dc.subject.keywordAuthordoxorubicin-
dc.subject.keywordAuthorcytotoxicity-
dc.subject.keywordAuthorRNA polymerase III-
dc.subject.keywordPlusPROTEIN-KINASE PKR-
dc.subject.keywordPlusPOLYMERASE-III-
dc.subject.keywordPlusEPIGENETIC REGULATION-
dc.subject.keywordPlusCANCER-
dc.subject.keywordPlusACTIVATION-
dc.subject.keywordPlusSUPPRESSOR-
dc.subject.keywordPlusMETHYLATION-
dc.subject.keywordPlusDOXORUBICIN-
dc.subject.keywordPlusPHARMACOKINETICS-
dc.subject.keywordPlusPHOSPHORYLATION-
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