GPN3 is a small GTPase that plays essential roles in RNA polymerase II (RNAPII) biogenesis and nuclear import. GPN3 directly associates with RNAPII subunits RPB7/RPB4 and the C-terminal domain, facilitating nuclear translocation of the polymerase complex 1. The protein functions cooperatively with other GPN family members, particularly GPN1, with mutual dependency between their protein levels 2. GPN3 undergoes regulated polyubiquitination on lysine 216 in the nucleus, targeting it for proteasomal degradation in a GPN1-inhibitable manner 3. Beyond its canonical role in transcriptional machinery assembly, GPN3 regulates clathrin-mediated endocytosis by interacting with clathrin light chain A (CLTA) and associated proteins, affecting EGFR internalization and prolonging growth factor signaling 4. GPN3 is essential for cell proliferation across various breast cancer cell lines regardless of transformation level, with knockdown causing cytoplasmic retention of RNAPII subunits 5. The protein is upregulated in multiple cancer types including non-small cell lung cancer and small-cell lung cancer, where it contributes to MYC-dependent ribosome biogenesis programs 46. High GPN3 expression correlates with poor prognosis in several cancer types, suggesting its potential as both a biomarker and therapeutic target.