PRJNA512015
Alternative splicing as a targetable modulator of APOBEC-mediated mutagenesis
Somatic mutations generated by the APOBEC3 enzymes are common in human cancers, but their burden varies within and between cancer types. We hypothesized that some of the observed variation in APOBEC-mediated mutagenesis could be explained by the isoform-specific expression of genes encoding relevant APOBEC3 enzymes. We confirmed this hypothesis by analysis in 7716 tumors representing 30 cancer types in The Cancer Genome Atlas and an additional 375 bladder tumors. Specifically, we found that skipping of exon 5 of APOBEC3B is significantly associated with decreased load of APOBEC-signature mutations. Treatment of cancer cell lines with pladienolide B, a drug that blocks the spliceosome engagement, increased skipping of exon 5 and decreased production of the mutagenic isoform of APOBEC3B on mRNA and protein level. We conclude that alternative splicing is an intrinsic, therapeutically targetable mechanism that modulates APOBEC-mediated mutagenesis.