POLR2A encodes the largest and catalytic subunit of RNA polymerase II, the central enzyme responsible for transcription of protein-coding genes and many non-coding RNAs in eukaryotes 1. Mechanistically, POLR2A functions in transcription initiation, elongation, and termination through its DNA-dependent RNA polymerase activity and interactions with regulatory proteins 23. The protein is subject to extensive post-translational modification, including ubiquitination and phosphorylation at serine 2, which regulate its stability and transcriptional activity 45. Clinically, POLR2A is implicated in multiple disease contexts. Mutations or hemizygous deletions of POLR2A frequently co-occur with TP53 loss in colorectal cancer, rendering cells vulnerable to POLR2A suppression and representing a therapeutic opportunity 1. In head and neck squamous cell carcinoma, the USP10 deubiquitinase stabilizes POLR2A, enabling transcriptional upregulation of SLC7A11 and ferroptosis resistance 5. POLR2A expression levels are dysregulated in multiple cancer types including esophageal carcinoma, glioblastoma, and triple-negative breast cancer, where they promote proliferation and affect immune responses 236. Additionally, POLR2A mutations associate with neurodevelopmental disorders, and POLR2A expression changes are implicated in EBV-mediated multiple sclerosis pathogenesis 7.