Targeting intron RNA processing for enhanced cancer therapy in triple-negative breast cancer (TNBC)

Abstract

Introns are found in all eukaryotes and are one of the defining characteristics of eukaryotes. After transcription, pre-mRNAs undergo splicing, and introns are excised as a lariat form. Since excised introns are degraded quickly after debranching, they have been considered as byproducts of gene expression, and their post-splicing role in the cells remains unclear. In this study, I find that the deficiency of the debranching enzyme, DBR1, in triple-negative breast cancer (TNBC) leads to immunogenic cell death due to the accumulation of intron lariats in the cytosol. In this context, introns hosting a large number of inverted repeats of Alus which can form double-stranded RNAs and trigger antiviral signaling are left undegraded. Prolonged DBR1 deficiency results in the cytosolic accumulation of intron lariats and increased interaction with dsRNA sensors of the innate immune system including protein kinase R (PKR). Furthermore, I find that the cytosolic release of intron lariats is facilitated by the cell cycle, particularly during the mitotic phase. Indeed, inducing mitotic arrest using paclitaxel accelerates the intron-mediated immunogenic cell death in DBR1-deficient TNBC via PKR activation. Together, these findings unveil the immunogenic function of intron lariats and provide the potential for enhancing the effect of antimitotic drugs in TNBC by targeting intron processing.