期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2016289118
关键词
DNA demethylation; double-stranded RNAs; noncoding RNA; RNA-binding protein; posttranscriptional regulation
资金
- Korean government Ministry of Science and ICT [NRF-2019R1C1C1006672, NRF-2013M3A9B5076486]
- KAIST Future Systems Healthcare Project [KAISTHEALTHCARE42]
This study uncovers the mechanism of viral mimicry and cell death triggered by decitabine through the activation of endogenous retroviruses (ERVs), highlighting the essential role of the double-stranded RNA-binding protein Staufen1 (Stau1) and providing a novel target for predicting the efficacy of DNMTis.
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.
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