Contributing factors to the oxidation-induced mutational landscape in human cells

Cameron Cordero, Kavi P. M. Mehta (), Tyler M. Weaver, Justin A. Ling, Bret D. Freudenthal (), David Cortez () and Steven A. Roberts ()
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Cameron Cordero: University of Vermont
Kavi P. M. Mehta: Vanderbilt University School of Medicine
Tyler M. Weaver: University of Kansas Medical Center
Justin A. Ling: University of Kansas Medical Center
Bret D. Freudenthal: University of Kansas Medical Center
David Cortez: Vanderbilt University School of Medicine
Steven A. Roberts: University of Vermont

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 8-oxoguanine (8-oxoG) is a common oxidative DNA lesion that causes G > T substitutions. Determinants of local and regional differences in 8-oxoG-induced mutability across genomes are currently unknown. Here, we show DNA oxidation induces G > T substitutions and insertion/deletion (INDEL) mutations in human cells and cancers. Potassium bromate (KBrO3)-induced 8-oxoGs occur with similar sequence preferences as their derived substitutions, indicating that the reactivity of specific oxidants dictates mutation sequence specificity. While 8-oxoG occurs uniformly across chromatin, 8-oxoG-induced mutations are elevated in compact genomic regions, within nucleosomes, and at inward facing guanines within strongly positioned nucleosomes. Cryo-electron microscopy structures of OGG1-nucleosome complexes indicate that these effects originate from OGG1’s ability to flip outward positioned 8-oxoG lesions into the catalytic pocket while inward facing lesions are occluded by the histone octamer. Mutation spectra from human cells with DNA repair deficiencies reveals contributions of a DNA repair network limiting 8-oxoG mutagenesis, where OGG1- and MUTYH-mediated base excision repair is supplemented by the replication-associated factors Pol η and HMCES. Transcriptional asymmetry of KBrO3-induced mutations in OGG1- and Pol η-deficient cells also demonstrates transcription-coupled repair can prevent 8-oxoG-induced mutation. Thus, oxidant chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.

Date: 2024
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DOI: 10.1038/s41467-024-55497-z

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