Polymerase ι promotes C>T substitutions in smoking models and in the platinum chemotherapy-induced SBS31 mutation...

DNA damage occasionally leads to mutations even in DNA repair-proficient cells via translesion synthesis (TLS), an efficient but error-prone DNA damage tolerance pathway. In the human genome, there are three closely related Y-family TLS polymerases (η, κ, and ι). Polymerase η is specialized for the error-free replication of UV adducts, while polymerase κ is known to replicate over various heterocyclic DNA adducts. The function of polymerase ι is less clear and this gene is missing from several vertebrate clades, yeast, most birds, and plants. Using wild-type and TLS polymerase (POLH, POLK, POLI) knockout human TK6 and RPE-1 cell lines and whole genome sequencing, we associate these polymerases to mutagenesis induced by the common chemotherapy agent cisplatin and the smoke-mimicking compound 4-nitroquinoline-1-oxide (4-NQO). We found that polymerase ι specifically introduces C>T mutations at both cisplatin and 4-NQO lesions, confirmed in two further cell lines. Using non-negative matrix factorization, we derived a polymerase ι-specific base substitution signature, which corresponds to COSMIC cancer mutational signature SBS31 with a cosine similarity of 0.97. By analyzing the mutational spectra in more than 3500 human metastatic tumors, we showed that SBS31 in platinum-treated samples and SBS92 in smoking-related cancers is associated with polymerase ι expression. Our study suggests an in vivo mutagenic function for polymerase ι and highlights its role in tissue-dependent chemotherapy-induced mutagenesis that may contribute to tumor heterogeneity.