The Integrator-PP2A complex at the crossroads of development and cancer

Transcriptional regulation relies on the Integrator complex and Protein Phosphatase 2A (PP2A), forming the Integrator–PP2A complex (INTAC). INTAC plays a pivotal role in RNA Polymerase II (RNAPII) pause-release, which regulates gene expression. Dysregulation of this system can have profound biological consequences. This thesis explores the PP2A-Integrator axis in two contexts: neurodevelopmental disorders linked to the R182W mutation in PPP2R1A, a core PP2A subunit, and prostate cancer progression involving loss of Integrator Subunit 6 (INTS6), a key INTAC component. In the first study, Induced Pluripotent Stem Cells (iPSCs) were used to model the PPP2R1A R182W mutation. The mutation caused morphological defects and impaired neural network formation. Transcriptomic and genomic analyses revealed dysregulation of neurogenesis-related genes and altered RNAPII binding. Mass spectrometry indicated disrupted interactions between PP2A and the Integrator complex, implicating defective PP2A-Integrator interactions in neurodevelopmental disorder pathogenesis. The second study focused on INTS6 in prostate cancer. Surprisingly, CRISPR/Cas9 knockout of INTS6 in DU145 cells reduced proliferation and tumor growth in vitro and in vivo, contrary to its tumor-suppressive role. Gene expression profiling showed disrupted pathways in cell cycle progression and differentiation. Analysis of DDX26B, an INTS6 homolog, revealed alternative splicing of exon 11 impacts its interaction with the Integrator complex and its ability to compensate for INTS6 loss. These findings underscore the critical role of PP2A-Integrator interactions in transcriptional regulation. Disrupting this axis—via PPP2R1A mutations or INTS6 loss—leads to significant gene expression changes, affecting differentiation and proliferation. The PP2A-Integrator complex emerges as a vital regulatory mechanism in both neurodevelopmental disorders and cancer.