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.