MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids
Summary
In response to perturbed transcription elongation, the MYC oncoprotein multimerizes and undergoes a phase transition. Here, we demonstrate that MYC globally relocalizes from its canonical positions on DNA to nascent RNA upon accumulation of intronic RNA. Upon binding to RNA, MYC forms multimers that concentrate the nuclear exosome, an RNA exonuclease, and its targeting complexes around double-stranded RNA and R-loops. MYC harbors four RNA-binding regions (RBRI-IV). RBRIII promotes MYC mult
Content
# MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids
*Published: 2026 Mar 5*
In response to perturbed transcription elongation, the MYC oncoprotein
multimerizes and undergoes a phase transition. Here, we demonstrate that MYC
globally relocalizes from its canonical positions on DNA to nascent RNA upon
accumulation of intronic RNA. Upon binding to RNA, MYC forms multimers that
concentrate the nuclear exosome, an RNA exonuclease, and its targeting complexes
around double-stranded RNA and R-loops. MYC harbors four RNA-binding regions
(RBRI-IV). RBRIII promotes MYC multimerization and is necessary for recruiting
the exosome to R-loops. RBRIII is dispensable for transcriptional activation and
pancreatic tumor cell proliferation in culture, but 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 activating the innate
immune kinase TBK1 via the TLR3 pattern recognition receptor. Our data
demonstrate that the phase transition of MYC is an RNA-driven stress response
that suppresses the accumulation of immunogenic RNA-DNA hybrids.
DOI: 10.1016/j.cell.2025.12.019