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

Autor: Cordero, Cameron, Mehta, Kavi P. M., Weaver, Tyler M., Ling, Justin A., Freudenthal, Bret D., Cortez, David, Roberts, Steven A.
Zdroj: Nature Communications; 12/23/2024, Vol. 15 Issue 1, p1-18, 18p
Abstrakt: 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. 8-oxoG is a common single-base DNA lesion caused by oxidative stress. Here, authors characterize the mutational signature of potassium bromate (KBrO3) exposure, the chromatin structural determinants of 8-oxoG-induced mutation and the mechanisms involved in the repair of KBrO3-induced 8-oxoG. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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