Integrator (INT) is a large protein complex that targets RNA polymerase II (RNAPII), terminating gene transcription in its earliest stages to regulate gene expression, including that of stress-responsive genes. Mutations to INT components are associated with many diseases, including cancer and neurodevelopmental disorders, though how they contribute to pathology has been unclear. Researchers led by Ludwig Harvard’s Karen Adelman reported in an April publication in Cell one possible mechanism for that. The loss of INT-mediated termination, they report, allows RNAPII to aberrantly escape into gene bodies, fully transcribing short genes but generating incomplete transcripts of longer ones. The researchers detail how this triggers the integrated stress response (ISR) in cells in two ways: by activating expression of short genes such as ATF3, a transcription factor that drives stress responses, and causing the generation of double-stranded (ds) RNAs. These dsRNAs, generated by the premature termination of transcription by immature RNAPII that escapes into gene bodies, are recognized by protein kinase R, which drives the activation of the transcription factor ATF4, a master regulator of ISR whose activation further sustains the stress response. Karen and her colleagues report that patient cells with INT mutations exhibit dsRNA accumulation and ISR activation, implicating chronic ISR in diseases caused by INT deficiency.
Integrator loss leads to dsRNA formation that triggers the integrated stress response
Cell, 2025 April 14