POLR2L (RNA polymerase II, I and III subunit L) is a highly conserved 7.6-kDa subunit shared by all three classes of nuclear RNA polymerase (Pol I, II, and III) 1. Located on chromosome 11, POLR2L contains a conserved atypical zinc-binding domain critical for multimeric RNA polymerase function 1. Beyond its structural role, POLR2L contributes to transcriptional regulation of protein-coding genes and non-coding RNAs, including tRNA, 5S rRNA, and mRNA 2. POLR2L dysregulation has emerged as significant in cancer pathogenesis, where it influences tumor growth, metastasis, and chemotherapy resistance through connections to PI3K-Akt, Wnt/β-catenin, and TGF-β signaling pathways 2. Additionally, POLR2L dysregulation is implicated in neurodegenerative diseases; proteomic analysis identified POLR2L among proteins dysregulated in parthanatos, a caspase-independent cell death pathway relevant to Parkinson's and Huntington's disease 3. In hematologic malignancies, POLR2L appears in prognostic signatures for acute myeloid leukemia 4 and as a hub gene in multiple sclerosis pathogenesis 5. These findings position POLR2L as both a fundamental transcriptional component and an emerging biomarker with therapeutic potential across multiple disease contexts.