한빛사논문
- 조회802
Yongsuk Kua,b,1, Joo-Hwan Parkc,d,1, Ryeongeun Choa,b,1, Yongki Leea,b, Hyoung-Min Parke, MinA Kima,b, Kyunghoon Hura,b, Soo Young Byunf, Jun Liuc,d, Young-suk Leeg, David Shumf, Dong-Yeop Shinc,d, Youngil Kohc,d, Je-Yoel Choe, Sung-Soo Yoonc,d, Junshik Hongc,d,2, and Yoosik Kima,b,2
aDepartment of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea; bKAIST Institute for Health Science and Technology (KIHST), KAIST, Daejeon 34141, Korea; cDepartment of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 03080, Korea; dCancer Research Institute, Seoul National University Hospital, Seoul 03080, Korea; eDepartment of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul 08826, Korea; fScreening Discovery Platform, Translation Research Division, Institut Pasteur Korea, Gyeonggi 13488, Korea; and gDepartment of Bio and Brain Engineering, KAIST, Daejeon 34141, Korea
1Y. Ku, J.-H.P., and R.C. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
DNA-methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used clinically to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERVs), which can induce immune response by acting as cellular double-stranded RNAs (dsRNAs). Yet, the posttranscriptional regulation of ERV dsRNAs remains uninvestigated. Here, we find that the viral mimicry and subsequent cell death in response to decitabine require the dsRNA-binding protein Staufen1 (Stau1). We show that Stau1 directly binds to ERV RNAs and stabilizes them in a genome-wide manner. Furthermore, Stau1-mediated stabilization requires a long noncoding RNA TINCR, which enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that MDS and AML patients with lower Stau1 and TINCR expressions exhibit inferior treatment outcomes to DNMTi therapy. Overall, our study reveals the posttranscriptional regulatory mechanism of ERVs and identifies the Stau1-TINCR complex as a potential target for predicting the efficacy of DNMTis and other drugs that rely on dsRNAs.
DNA demethylation, double-stranded RNAs, noncoding RNA, RNA-binding protein, posttranscriptional regulation
논문정보
- Research article
- 2021년 03월 (BRIC 등록일 2021-04-08)
- 국내 연구진
- 생명과학 > 분자생물학
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