MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids

Area of Science:

• Molecular Biology
• Oncology
• Immunology

Background:

• The MYC oncoprotein plays a critical role in cell proliferation and is frequently dysregulated in cancer.
• MYC's function is linked to transcription, but its dynamic behavior under stress is not fully understood.
• Accumulation of intronic RNA can trigger cellular responses involving MYC.

Purpose of the Study:

• To investigate the MYC oncoprotein's response to perturbed transcription elongation and RNA accumulation.
• To elucidate the mechanism by which MYC undergoes phase transition and its functional consequences.
• To determine the role of MYC's RNA-binding regions in its stress response and tumor growth.

Main Methods:

• Global relocalization studies of MYC in response to intronic RNA accumulation.
• Analysis of MYC multimerization and its interaction with RNA, nuclear exosome, and double-stranded RNA/R-loops.
• Functional characterization of MYC's RNA-binding regions (RBRI-IV), particularly RBRIII, in cellular assays and in vivo tumor models.
• Assessment of MYC's role in suppressing RNA-DNA hybrids and preventing innate immune activation via TBK1/TLR3 pathway.

Main Results:

• MYC globally relocalizes from DNA to nascent RNA upon intronic RNA accumulation, forming RNA-driven phase transitions.
• MYC multimerization, mediated by RBRIII, concentrates the nuclear exosome complex around double-stranded RNA and R-loops.
• RBRIII is essential for MYC's role in suppressing RNA-DNA hybrids and preventing TBK1 activation by TLR3, but dispensable for basal proliferation.
• RBRIII is indispensable for sustaining tumor growth in vivo, highlighting its critical role in MYC-driven oncogenesis.

Conclusions:

• The phase transition of MYC is an RNA-driven stress response critical for preventing the accumulation of immunogenic RNA-DNA hybrids.
• MYC's RBRIII domain is a key mediator of this stress response, suppressing R-loops and innate immune activation.
• Targeting MYC's RNA-binding capabilities, particularly RBRIII, may offer novel therapeutic strategies for MYC-driven cancers.