POLH encodes DNA polymerase eta (polη), a Y-family DNA polymerase specialized in translesion synthesis (TLS)—the ability to accurately replicate across DNA lesions that block replication forks 12. Polη is particularly important for replicating past UV-induced pyrimidine dimers and cisplatin-induced intrastrand crosslinks, inserting correct nucleotides opposite these lesions 34. Due to its low processivity, polη cooperates with the POLZ complex (containing REV3L, REV7, POLD2, and POLD3) to complete lesion bypass 5. Polη exhibits error-prone activity on undamaged DNA and may contribute to hypermutation at immunoglobulin genes, though it forms covalent complexes with abasic sites that limit mutagenesis during base excision repair 6. Clinical significance of POLH extends beyond its essential role in xeroderma pigmentosum variant (XPV), where loss-of-function mutations cause severe UV sensitivity and skin cancer predisposition 5. Germline and somatic POLH variants impair polymerase activity and cellular tolerance to UV radiation and cisplatin 4. In cancer contexts, elevated POLH expression—regulated by alternative polyadenylation producing short 3'UTR transcripts that escape microRNA repression—confers cisplatin resistance in lung and bladder cancers 7. RAD18 O-GlcNAcylation promotes polη focus formation at DNA damage sites, facilitating both TLS and homologous recombination repair 8. Additionally, G-quadruplex-induced replication stress depends on polη throughout S phase for fork restart and micronuclei prevention 9.