Non-canonical immune response to inhibition of DNA methylation via stabilization of dsRNAs from endogenous retroviruses

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DNA-methyltransferase inhibitors (DNMTis), such as decitabine, are usedclinically 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). Here, we find that the viral mimicry and subsequent cell death in response to decitabine requires dsRNA-binding protein Staufen1 (Stau1). We show that Stau1 directly binds to ERV RNAs in a genome-wide manner and stabilizes them. Furthermore, Stau1-mediated stabilization requires a long non-coding RNA TINCR, which enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that MDS/AML patients with lower Stau1 and TINCR expressions exhibit inferior treatment outcomes to DNMTi therapy. Overall, our study reveals the post-transcriptional regulatory mechanism of ERVs and identifies Stau1-TINCR complex as a potential target for predicting the efficacy of DNMTis and other drugs that rely on dsRNAs.
Publisher
Korean Society for Molecular and Cellular Biology
Issue Date
2020-10-06
Language
English
Citation

2020 International conference: Korean Society for Molecular and Cellular Biology, pp.73

URI
http://hdl.handle.net/10203/277899
Appears in Collection
CBE-Conference Papers(학술회의논문)
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