GABPA recruits the Integrator endonuclease complex to promote transcription elongation.

Transcription factors (TFs) coordinate gene regulatory programs essential for cell identity, yet how individual TFs modulate distinct steps of the transcription cycle remains incompletely understood. GA-binding protein alpha (GABPA), an erythroblast transformation-specific (ETS)-family TF, is crucial for naïve pluripotency during mouse preimplantation development, but its molecular functions remain elusive. Using an acute protein degradation system, we dissected GABPA activity with high temporal resolution, thereby identifying its primary transcriptional targets and underlying mechanisms while minimizing the secondary effects associated with conventional gene knockout approaches. We found that GABPA is essential for mouse embryonic stem cell (mESC) viability through a previously unrecognized mechanism independent of its canonical heterotetrameric partner, GABPB. Mechanistically, GABPA physically interacts with the INTS4/9/11 endonuclease module of the Integrator complex to promote the productive elongation of RNA polymerase II (Pol II) at genes involved in ribonucleoprotein complex biogenesis. Acute loss of GABPA leads to the accumulation of promoter-proximal Pol II and a reduction in Ser2-phosphorylated Pol II across gene bodies, indicating defective transcriptional elongation, whereas prolonged depletion leads to a broader collapse of transcription-associated chromatin features and the general transcription machinery. Together, our study redefines GABPA as a multifaceted transcriptional regulator that acts independently of GABPB and provides a framework for the temporally resolved analysis of TF function in stem cell biology.