POLN encodes DNA polymerase nu, a low-fidelity A-family DNA polymerase with specialized roles in DNA repair and translesion synthesis. POLN catalyzes considerable misincorporation, particularly inserting dTTP opposite template G (frequency 0.45) and dGTP opposite template T, making it the least accurate polymerase in the POLG/POLN/POLQ family 1. Despite its error-prone nature, POLN performs accurate translesion synthesis past thymine glycol lesions and efficiently displaces DNA strands 1. POLN participates in interstrand cross-link (ICL) repair through FANCD2-mediated pathways and functions in homologous recombination repair via complex formation with HELQ helicase, providing cellular protection against DNA cross-links 2. POLN is predominantly expressed in testis and has restricted tissue distribution, with demonstrated involvement in meiotic recombination at specific substrate architectures 3. Clinically, rare POLN mutations (P577L, R303Q, F545C) confer significantly increased risk for familial nasopharyngeal carcinoma by reducing protein stability and impairing Epstein-Barr virus lytic replication control 4. Additionally, POLN variants associate with elevated prostate cancer risk in Chinese populations 5. These findings establish POLN as a specialized polymerase with tissue-restricted expression supporting genome maintenance during reproduction and a disease susceptibility gene in cancer development.