Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs

Ku, Y.; Park, J.-H.; Cho, R.; Lee, Y.; Park, H.-M.; Kim, M.; Hur, K.; Byun, S. Y.; Liu, J.; Shum, D.; Shin, D.-Y.; Koh, Y.; Cho, J.-Y.; Yoon, S.-S.; Hong, J.; Kim, Y.

doi:10.1101/2020.06.21.163857

bioRxiv · 10.1101/2020.06.21.163857

Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs

Ku, Y.·Park, J.-H.·Cho, R.·Lee, Y.·Park, H.-M.·Kim, M.·Hur, K.·Byun, S. Y.·Liu, J.·Shum, D.·Shin, D.-Y.·Koh, Y.·Cho, J.-Y.·Yoon, S.-S.·Hong, J.·Kim, Y.

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Abstract

5-Aza-2'-deoxycytidine, also known as decitabine, is a DNA-methyltransferase inhibitor (DNMTi) used to treat acute myeloid leukemia (AML). Decitabine activates the transcription of endogenous retroviruses (ERV), which can induce an immune response by acting as cellular double-stranded RNAs (dsRNAs). Here, we employ an image-based screening platform to identify dsRNA-binding factors that mediate the downstream effect of ERV induction. We find that Staufen1 (Stau1) knockdown decreases the interferon signature and rescues decitabine-mediated cell death. Moreover, Stau1 directly binds to ERV RNAs and stabilizes them, together with a long non-coding RNA TINCR. We further show that TINCR enhances the interaction between Stau1 and ERV RNAs. Analysis of a clinical patient cohort reveals that AML patients with low Stau1 and TINCR expressions exhibits inferior treatment outcomes to the DNMTi therapy. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA-binding proteins for access to their common dsRNA targets. HIGHLIHGTSO_LIImage-based RNAi screening reveals multiple dsRBPs regulate response to decitabine C_LIO_LIStau1 binds to ERV RNAs and affects their stability and subcellular localization C_LIO_LITINCR binds to Stau1 and enhances Stau1-ERV interactions C_LIO_LIAML/MDS patients with low Stau1 and TINCR expressions show poor response to DNMTis C_LI

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Ku, Y., Park, J.-H., Cho, R., Lee, Y., Park, H.-M., Kim, M., Hur, K., Byun, S. Y., Liu, J., Shum, D., Shin, D.-Y., Koh, Y., Cho, J.-Y., Yoon, S.-S., Hong, J., Kim, Y.. 2020-06-21. Non-canonical immune response to the inhibition of DNA methylation via stabilization of endogenous retrovirus dsRNAs. https://doi.org/10.1101/2020.06.21.163857

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