HnRNP C binding to inverted Alu elements protects the transcriptome from pre-mRNA circularization

Back-splicing is a non-canonical splicing event that drives the biogenesis of circular RNAs (circRNAs). Although the molecular mechanisms underlying circRNA biogenesis have been partially elucidated, how this process is globally regulated in tumors that show a general repression of circRNAs, such as medulloblastoma (MB), has not been fully investigated. Herein, we uncover a hnRNP C-dependent mechanism that represses a broad repertoire of circRNAs in Group 3 MB. HnRNP C binds Alu elements and prevents non-colinear splicing, thus repressing circularization of pre-mRNA transcripts. Expression of hnRNP C modulates the balance between linear and circular splicing and guarantees efficient expression of genes that sustain the oncogenic phenotype of Group 3 MB cells. Remarkably, in the absence of hnRNP C, the introns flanking the circularizing exons generated cytoplasmic dsRNAs through base-pairing of inverted Alu elements and, consequently, triggered an interferon-induced antiviral defense mechanism. These findings unveil the role of hnRNP C as guardian of transcriptome integrity by repressing circRNA biogenesis and suggest that targeting hnRNP C in Group 3 MB may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.