Disrupting MYC RNA Interactions Promotes Tumor Regression

While MYC is commonly regarded as an oncoprotein that localizes to promoters and drives transcription of protumorigenic gene programs, emerging studies suggest that its role in cancer may extend beyond its DNA-binding capacity. However, the mechanisms and consequences of DNA-independent MYC activity remain poorly understood. Uhl, Aziba, Löbbert, and colleagues sought to address this by using multiple cancer models to characterize MYC RNA interactions. In human chronic myeloid leukemia and osteosarcoma cell lines, single-end enhanced crosslinking and immunoprecipitation (seCLIP) sequencing analysis revealed that the majority of MYC-bound sites were located within intronic RNA. Further seCLIP experiments indicated that transcriptional stress may influence these interactions, as perturbing transcription elongation increased the number of MYC RNA-binding sites as well as the amount of MYC bound to the RNA. Parallel DNA–RNA immunoprecipitation with cDNA (DRIPc) sequencing analyses identified an enrichment of R-loops at these sites, suggesting that MYC localizes to RNA–DNA hybrids in response to stress. In order to functionally study these interactions, RNA binding was mapped along a full-length MYC peptide microarray. Amongst the four regions identified, RNA binding region III (RBRIII) exhibited the strongest affinity. Mutagenesis of multiple residues within this region yielded cells (RBRIIImut) with defects in RNA binding confirmed by fluorescence anisotropy and eCLIP sequencing. Interestingly, while stable expression of mutant RBRIII in mouse pancreatic ductal adenocarcinoma cells was insufficient to elicit a growth defect in vitro, RBRIIImut tumors regressed in an immunocompetent, syngeneic mouse model, indicating that RBRIII is required to support tumor progression in vivo. RNA sequencing data revealed that, when compared with WT controls, RBRIIImut cells exhibited increased expression of genes regulated by transcription factors involved in innate immune signaling. In line with these data, mutation of RBRIII activated signaling cascades downstream of Toll-like receptor 3 (TLR3), and increased interactions between TLR3 and R-loops, known activators of this pattern recognition receptor. Taken together, this study identifies an RNA-dependent mechanism by which MYC regulates innate immune signaling and tumor dynamics.Uhl L, Aziba A, Löbbert S, Russell T, Krenz B, Montesinos F, et al. MYC binding to nascent RNA suppresses innate immune signaling by R-loop-derived RNA-DNA hybrids. Cell 2026 Jan 22 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.