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

• 成果类型: Article
• 署名作者: Engel, Botond; Szikriszt, Bernadett; Gyure, Zsolt; Sale, Julian E.; Szuts, David; Nemeth, Eszter
• 署名单位: HUN-REN; HUN-REN Research Centre for Natural Sciences; Semmelweis University; MRC Laboratory Molecular Biology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2526551123
• 发表日期: 2026-08-11
• 页码: e2526551123
• 关键词: polymerase iota; translesion synthesis; mutagenesis; chemotherapy; smoking; POL-IOTA; dna; cancer; eta; opposite; LESION; cells

摘要

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 (eta, kappa, and iota). Polymerase eta is specialized for the error-free replication of UV adducts, while polymerase kappa is known to replicate over various heterocyclic DNA adducts. The function of polymerase iota 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 iota 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 iota-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 iota expression. Our study suggests an in vivo mutagenic function for polymerase iota and highlights its role in tissue-dependent chemotherapy-induced mutagenesis that may contribute to tumor heterogeneity.