{"doi":"10.1016/j.jbc.2023.105067","title":"The peroxidation-derived DNA adduct, 6-oxo-M1dG, is a strong block to replication by human DNA polymerase η","abstract":"The DNA adduct 6-oxo-M 1 dG, (3-(2'-deoxy-β-D-erythro-pentofuranosyl)-6-oxo-pyrimido(1,2alpha)purin-10(3H)-one) is formed in the genome via oxidation of the peroxidation-derived adduct M 1 dG. However, the effect of 6-oxo-M 1 dG adducts on subsequent DNA replication is unclear. Here we investigated the ability of the human Y-family polymerase hPol η to bypass 6-oxo-M 1 dG. Using steady-state kinetics and analysis of DNA extension products by LC-MS/MS, we found hPol η preferentially inserts a dAMP or dGMP nucleotide into primer-templates across from the 6-oxo-M 1 dG adduct, with dGMP being slightly preferred. We also show primer-templates with a 3′-terminal dGMP or dAMP across from 6-oxo-M 1 dG were extended to a greater degree than primers with a dCMP or dTMP across from the adduct. In addition, we explored the structural basis for bypass of 6-oxo-M 1 dG by hPol η using X-ray crystallography of both an insertion-stage and an extension-stage complex. In the insertion-stage complex, we observed that the incoming dCTP opposite 6-oxo-M 1 dG, although present during crystallization, was not present in the active site. We found the adduct does not interact with residues in the hPol η active site, but rather forms stacking interactions with the base pair immediately 3′ to the adduct. In the extension-stage complex, we observed the 3′ hydroxyl group of the primer strand dGMP across from 6-oxo-M 1 dG is not positioned correctly to form a phosphodiester bond with the incoming dCTP. Taken together, these results indicate 6-oxo-M 1 dG forms a strong block to DNA replication by hPol η and provide a structural basis for its blocking ability.","journal":"Journal of Biological Chemistry","year":2023,"id":381005,"datarank":0.25719716285107813,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.015781475985963037,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.015781475985963037,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":436820,"name":"Pradeep S. Pallan","orcid":null,"position":1,"is_corresponding":false},{"id":390887,"name":"Philip J. Kingsley","orcid":"0000-0002-5470-4340","position":2,"is_corresponding":false},{"id":1147030,"name":"Nikhil Kamdar","orcid":null,"position":3,"is_corresponding":false},{"id":435753,"name":"Martin Egli","orcid":"0000-0003-4145-356X","position":4,"is_corresponding":false},{"id":318552,"name":"Lawrence J. Marnett","orcid":"0000-0002-7834-6285","position":5,"is_corresponding":false},{"id":1147029,"name":"Robyn Richie-Jannetta","orcid":null,"position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:17:08.831117Z","pmid":"37468099","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}