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

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 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE281778 | GEO | 2026/02/09

REPOSITORIES: GEO

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