Analysis of cytosine deamination events in excision repair sequencing reads reveals mechanisms of incision site selection in NER

Morledge-Hampton, Benjamin; Kalyanaraman, Ananth; Wyrick, John J

doi:10.1093/nar/gkad1195

Cited by 3 publications

(1 citation statement)

References 67 publications

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“…Mutations and lesions were intersected with strongly positioned nucleosome dyads following the protocol outlined in 77 in a 1000 base-pair (bp) window. Expected counts were calculated using genomic trinucleotide mutation or lesion frequencies multiplied by the occurrence of those contexts at each position in the dyad map.…”

Section: Correlation Of Indel Signature With Sbs18mentioning

confidence: 99%

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Cordero,

Mehta,

Weaver

et al. 2024

Preprint

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Abstract8-oxoguanine (8-oxoG) is a common oxidative DNA lesion, which causes G>T substitutions that compose COSMIC single base substitution signature 18 (SBS18) in human cancers. Determinants of local and regional differences in 8-oxoG-induced mutability are currently unknown. To uncover factors influencing the topology of 8-oxoG-induced mutations, we assessed spontaneous and KBrO3-induced 8-oxoG mutagenesis in human cell lines. KBrO3exposure produced a SBS18-like substitution spectrum and a distinct never-before reported INDEL signature that we also observed in human cancers. KBrO3-induced 8-oxoG lesions occurred with similar sequence preference as KBrO3-induced substitutions, indicating that the reactivity of specific reactive oxygen species (ROS) dictates the trinucleotide motif specificity for 8-oxoG-induced mutagenesis. While 8-oxoG lesions occurred relatively uniformly across chromatin states and nucleosomes, 8-oxoG-induced mutations occurred more frequently in more compact regions of the genome, within nucleosomal DNA, and at inward facing guanines within strongly positioned nucleosomes. Cryo-EM structures of OGG1 bound to nucleosomes indicate that these effects originate from OGG1’s ability to flip outward positioned 8-oxoG lesions into the catalytic pocket with only minor alterations to nucleosome structure, while inward facing lesions occluded by the histone octamer are unrecognized. Mutation spectra from cells with DNA repair deficiencies revealed a hierarchical DNA repair network limiting 8-oxoG mutagenesis in human cells, where OGG1– and MUTY-mediated BER is supplemented by replication-associated factors participating in tolerance of 8-oxoG or derived repair intermediates (i.e. Pol η and HMCES). Surprisingly, analysis of transcriptional asymmetry of KBrO3-induced mutations demonstrated transcription-coupled repair of 8-oxoG in Pol η-deficient cells. Thus, radical chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.

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Section: Correlation Of Indel Signature With Sbs18mentioning

confidence: 99%

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Cordero,

Mehta,

Weaver

et al. 2024

Preprint

View full text Add to dashboard Cite

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

Cordero,

Mehta,

Weaver

et al. 2024

Nat Commun

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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 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.

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Nucleotide excision repair of aflatoxin-induced DNA damage within the 3D human genome organization

Wu,

Adeel,

Xia

et al. 2024

Nucleic Acids Research

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Aflatoxin B1 (AFB1), a potent mycotoxin, is one of the environmental risk factors that cause liver cancer. In the liver, the bioactivated AFB1 intercalates into the DNA double helix to form a bulky DNA adduct which will lead to mutation if left unrepaired. Here, we adapted the tXR-seq method to measure the nucleotide excision repair of AFB1-induced DNA adducts at single-nucleotide resolution on a genome-wide scale, and compared it with repair data obtained from conventional UV-damage XR-seq. Our results showed that transcription-coupled repair plays a major role in the damage removal process. We further analyzed the distribution of nucleotide excision repair sites for AFB1-induced DNA adducts within the 3D human genome organization. Our analysis revealed a heterogeneous AFB1–dG repair across four different organization levels, including chromosome territories, A/B compartments, TADs, and chromatin loops. We found that chromosomes positioned closer to the nuclear center and regions within A compartments have higher levels of nucleotide excision repair. Notably, we observed high repair activity around both TAD boundaries and loop anchors. These findings provide insights into the complex interplay between AFB1-induced DNA damage repair, transcription, and 3D genome organization, shedding light on the mechanisms underlying AFB1-induced mutagenesis.

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Analysis of cytosine deamination events in excision repair sequencing reads reveals mechanisms of incision site selection in NER

Cited by 3 publications

References 67 publications

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

Hierarchical determinants of the oxidation-induced mutational landscape in human cells

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

Nucleotide excision repair of aflatoxin-induced DNA damage within the 3D human genome organization

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