POLI (DNA polymerase iota) is an error-prone DNA polymerase specialized in translesion synthesis (TLS), enabling DNA replication to proceed when normal high-fidelity polymerases stall at DNA lesions 1. POLI exhibits distinctive catalytic properties: it inserts the correct base with high fidelity opposite adenosine templates by favoring Hoogsteen base-pairing, but shows low fidelity opposite thymidine templates, preferentially incorporating guanosine 1. The enzyme can form a Schiff base with 5'-deoxyribose phosphate at abasic sites, though its lyase activity remains unclear 1. Unlike its evolutionary relative Drosophila POLI, mammalian POLI exhibits reduced efficiency at lesion bypass, suggesting evolutionary specialization toward other cellular functions 1. POLI operates within a hierarchical DNA damage tolerance network coordinated by p53 levels, working alongside other TLS polymerases and fork-remodeling factors to modulate replication rates at damaged sites 2. Beyond canonical TLS, POLI may contribute to immunoglobulin gene hypermutation, though this role requires further characterization 1. The specialized properties of mammalian POLI indicate adaptation to cellular functions beyond simple lesion bypass, likely reflecting its role in maintaining genomic stability under replication stress while minimizing mutagenesis.