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TitleContributing factors to the oxidation-induced mutational landscape in human cells.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10722, Year 2024
Publish dateDec 23, 2024
AuthorsCameron Cordero / Kavi P M Mehta / Tyler M Weaver / Justin A Ling / Bret D Freudenthal / David Cortez / Steven A Roberts /
PubMed Abstract8-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 ...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 (KBrO)-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 KBrO-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.
External linksNat Commun / PubMed:39715760 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.7 Å
Structure data

43595

8vws

EMDB-43595, PDB-8vws:
Nucleosome containing 8oxoG at SHL-6
Method: EM (single particle) / Resolution: 3.1 Å

43596

8vwt

EMDB-43596, PDB-8vwt:
OGG1 bound to a nucleosome containing 8oxoG at SHL-6 (composite map)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43597: OGG1 bound to a nucleosome containing 8oxoG at SHL-6 (consensus map)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43598: OGG1 bound to a nucleosome containing 8oxoG at SHL-6 (NCP local refine)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43599: OGG1 bound to a nucleosome containing 8oxoG at SHL-6 (OGG1/DNA local refine)
Method: EM (single particle) / Resolution: 3.4 Å

43600

8vwu

EMDB-43600, PDB-8vwu:
Nucleosome containing 8oxoG at SHL4
Method: EM (single particle) / Resolution: 3.0 Å

43601

8vwv

EMDB-43601, PDB-8vwv:
OGG1 bound to a nucleosome containing 8oxoG at SHL4 (composite map)
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43602: OGG1 bound to a nucleosome containing 8oxoG at SHL4 (consensus map)
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-43603: OGG1 bound to a nucleosome containing 8oxoG at SHL4 (OGG1/DNA local refine)
Method: EM (single particle) / Resolution: 3.7 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA BINDING PROTEIN/DNA / Nucleosome / 8-oxo-guanine DNA Glycosylase I / DNA Repair / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex / OGG1

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