RNA dicing promotes the expression of an oncogenic JAK1 isoform.

Abstract

The translation of an mRNA transcript is traditionally thought to be limited to its open reading frames (ORFs). However, recent findings reveal a more complex reality in which the proteome vastly exceeds transcriptome limits. Here, we demonstrate that JAK1 mRNA can be cleaved into a truncated, uncapped form with a shorter ORF, leading to the translation of the JH1 kinase domain independently of other domains, a process we term "RNA dicing." Canonical and diced JAK1 variants differently impact cell proliferation and tumorigenesis, with the balance of these isoforms altered in tumorigenesis and in response to IFN-γ. Analyzing JAK1 nonsense mutations in endometrial tumors reveals that mutations inhibit the tumor-suppressive functions of canonical JAK1 while enhancing the oncogenic diced JH1 domain. This results in a better response to the JAK1 inhibitor momelotinib, highlighting RNA dicing's role in patient stratification. Our findings show that RNA dicing diversifies mRNA products, significantly impacting biological functions.