Pan-cancer multi-omics analysis reveals upregulation of the POLE2 subunit of DNA polymerase epsilon and its associations with patient survival and cellular pathways beyond DNA replication.

DNA polymerase epsilon (Polε) is essential for high-fidelity leading-strand synthesis. It comprises a catalytic subunit, POLE, and three accessory subunits, including POLE2. In contrast to POLE, the biological functions and clinical significance of POLE2 remain unexplored. POLE2 is vital for the assembly of Polε and for interactions with the CMG helicase. Yeast studies show that dysfunction of its ortholog, Dpb2, causes genomic instability and impaired cell cycle progression. To investigate the significance of POLE2, this study provides a comprehensive multi-omics analysis across tumor types. We show that POLE2 upregulation is associated with decreased overall survival in a cancer-type-specific manner. Its expression levels, rather than copy number variation (CNV), emerge as a more reliable prognostic marker. POLE2 expression regulatory mechanisms include promoter methylation, isoform usage, and epigenetic regulators. Elevated POLE2 messenger RNA levels rarely translate into increased protein levels, possibly because of abundant non-coding isoforms. Co-expression and pathway enrichment analyses reveal an association between POLE2 and transcriptional regulation involving E2F, EZH2, and RB. Our findings highlight POLE2 as a contributor to genome stability, a candidate cancer biomarker, and a possible therapeutic target.