POLM (DNA polymerase mu) is a specialized gap-filling polymerase that plays critical roles in DNA double-strand break repair through the non-homologous end joining (NHEJ) pathway 12. The enzyme demonstrates a unique function in creating precise 1 bp insertions that match the nucleotide on the protospacer-adjacent motif side of Cas9-generated breaks, working in cooperation with DNA-PKcs protein 12. POLM is upregulated in response to DNA damage, as demonstrated in H. pylori-infected gastric tissue where it showed 15.72-fold increased expression in 63% of infected patients compared to controls, suggesting activation of NHEJ repair mechanisms 3. The G312R variant of POLM has pathological significance in ovarian cancer, promoting genomic instability through enhanced ribonucleotide insertion and activating the COL11A1-NF-κB signaling axis, which contributes to tumor progression and chemotherapy resistance 4. In colorectal cancer, POLM is co-regulated with other DNA repair genes including BRCA1, BRCA2, and mismatch repair factors, indicating its integration into broader DNA damage response networks 5. These findings establish POLM as both a key DNA repair enzyme and a potential therapeutic target in cancer treatment.