PhD Scientific Days 2026

Pathological and Oncological Sciences 2.

The Role of Polymerase ⍳ in Chemotherapy- and Smoking-induced Mutagenesis

Name of the presenter

Engel, Botond

Institute/workplace of the presenter

HUN-REN Research Centre for Natural Sciences, Institute of Molecular Life Sciences

Authors

Engel Botond¹, Szikriszt Bernadett¹, Szüts Dávid¹, Németh Eszter¹
1: HUN-REN Research Centre for Natural Sciences, Institute of Molecular Life Sciences

Text of the abstract

Introduction: DNA damage can be directly induced by exposure to chemical compounds such as tobacco smoke and cisplatin. Tobacco smoking is a major contributor to lung cancer development, whereas cisplatin, a chemotherapeutic agent, can induce mutations that promote secondary tumour formation and chemotherapy resistance. Translesion synthesis (TLS) polymerases κ, ι, and η are specialized in replicating across DNA lesions that block normal replication. However, these enzymes have lower fidelity than replicative polymerases and can occasionally incorporate incorrect nucleotides, thereby contributing to mutagenesis.

Aims: We aimed to investigate the in vivo roles of TLS polymerases in genomic instability induced by smoking and chemotherapy.

Methods: Mutagenesis induced by cisplatin and 4-nitroquinoline 1-oxide (4-NQO), a compound that mimics the effects of smoking, was investigated in wild type TK6 human lymphocyte cell lines and in TLS knockout cell lines (POLK-/-, POLH-/- and POLI-/-). We generated a DT40 chicken lymphocyte cell line carrying a human POLI transgene to confirm the observed POLI-/- phenotype. We performed induced mutagenesis assay by treating cell cultures with the IC50 concentration four times, followed by whole genome sequencing of treated subclones. We then analysed the mutation spectra, extracted mutational signatures, and investigated the genomic properties of the mutations. We analysed WGS and RNA-seq data of more than 3500 metastatic human tumours, which was received upon request from the Hartwig Medical Foundation.

Results: Strikingly, we discovered that polymerase ι alone is responsible for introducing C>T mutations at both cisplatin- and 4-NQO-induced lesions. We identified a polymerase ι–specific base substitution signature that corresponds to mutational signature SBS31 in the COSMIC database. By analysing the mutational spectra in the human metastatic tumours, we showed that SBS92 in smoking-related cancers and SBS31 in platinum therapy treated samples is associated with polymerase ι expression.

Conclusion: Our study explores how polymerase  contributes to tissue-dependent chemotherapy-induced mutagenesis that may drive to tumour heterogeneity. Thus, we identified one of the first in vivo functions of polymerase ι.

Funding: NKFIH grants PD134818, STARTING-150378, K134779, K142385 and PharmaLab-RRF-2.3.1-21-2022-00015.