Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis

Durfee, C.; Bergstrom, E. N.; Diaz-Gay, M.; Zhou, Y.; Temiz, N. A.; Ibrahim, M. A.; Nandi, S. P.; Wang, Y.; Liu, X.; Steele, C. D.; Proehl, J.; Vogel, R. I.; Argyris, P. P.; Alexandrov, L. B.; Harris, R.

doi:10.1101/2025.01.18.633716

bioRxiv · 10.1101/2025.01.18.633716

Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis

Durfee, C.·Bergstrom, E. N.·Diaz-Gay, M.·Zhou, Y.·Temiz, N. A.·Ibrahim, M. A.·Nandi, S. P.·Wang, Y.·Liu, X.·Steele, C. D.·Proehl, J.·Vogel, R. I.·Argyris, P. P.·Alexandrov, L. B.·Harris, R.

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Abstract

Mutational processes are thought to act independently and additively. We challenge this view by demonstrating that DNA-adducting agents sensitize the genome to mutagenesis by APOBEC enzymes. A model tobacco carcinogen (NQO) triggers a 100-fold increase in APOBEC3B- catalyzed signature mutations and elevates oral carcinoma levels in vivo. A hallmark of this unidirectional synergy is strand-coordinated pairs of APOBEC signature mutations within 32nt of each other (didyma). Biochemical experiments show that APOBEC3B can catalyze didyma formation, and genetic studies demonstrate requirements for APOBEC3B and functional nucleotide excision repair (XPA in human cells and Rad14 in yeast). Analyses of lung and head & neck cancers show that APOBEC mutagenesis and didyma are elevated in tumors from smokers compared to non-smokers. Additional tumor types with links to DNA-adducting agents also exhibit didyma. These studies support a model in which DNA-adducting carcinogens activate nucleotide excision repair and amplify mutagenesis by APOBEC enzymes in cancer.

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Durfee, C., Bergstrom, E. N., Diaz-Gay, M., Zhou, Y., Temiz, N. A., Ibrahim, M. A., Nandi, S. P., Wang, Y., Liu, X., Steele, C. D., Proehl, J., Vogel, R. I., Argyris, P. P., Alexandrov, L. B., Harris, R.. 2025-01-22. Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis. https://doi.org/10.1101/2025.01.18.633716

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