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

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.