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Binding of MYC to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids [DRIPc]

ABSTRACT: In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition; the underlying mechanisms and their function are unknown. Here, we show that MYC relocalizes from its canonical location on DNA to RNA in response to the accumulation of intronic RNA. MYC directly binds RNA, which promotes its multimerization. MYC multimers concentrate the nuclear exosome, a 3'-5' RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops. RNA binding of MYC suppresses activation of the innate immune kinase TBK1. Upon MYC depletion, intron-derived dsRNAs, including RNA derived from small nucleolar RNAs, and RNA-DNA hybrids accumulate on TLR3, a pattern recognition receptor that activates TBK1. RNA binding of MYC is required to suppress the accumulation of R-loop-derived RNA-DNA hybrids on TLR3. Our data show that the phase transition of MYC is an RNA-driven stress response that suppresses the accumulation of immunogenic RNAs.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE281612 | GEO | 2026/02/09

REPOSITORIES: GEO

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Binding of MYC to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids [seCLIP]

Project description:In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition. The underlying mechanisms and their function are unknown. Here, we demonstrate that MYC globally relocalizes from its canonical positions on DNA to nascent RNA in response to the accumulation of intronic RNA. Binding of MYC to RNA induces MYC to form multimers that concentrate the nuclear exosome - a 3'-5' RNA exonuclease - and its targeting complexes around double-stranded RNA and R-loops. MYC harbors four RNA-binding regions (RBRI–IV), which overlap with evolutionarily conserved regions. Of these, RBRIII promotes MYC multimerization and is necessary for recruiting the exosome to R-loops. While RBRIII is dispensable for MYC-dependent transcriptional activation and pancreatic tumor cell proliferation in culture, it is indispensable for sustaining tumor growth in vivo. Via RBRIII, MYC suppresses the accumulation of R-loop-derived RNA-DNA hybrids and prevents them from binding to the pattern recognition receptor TLR3 and activating the innate immune kinase TBK1. Our data demonstrate that MYC has mechanistically distinct functions in transcription and RNA metabolism, and that its phase transition is an RNA-driven stress response that suppresses the accumulation of immunogenic RNA-DNA hybrids.

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Binding of MYC to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids [DRIPc]

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