{"doi":"10.1101/gr.277430.122","title":"Genetic inhibitors of APOBEC3B-induced mutagenesis","abstract":"The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the homologous recombination (HR)-dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single-stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18-RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display three- to fourfold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.","journal":"Genome Research","year":2023,"id":390417,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.967,"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":1162729,"name":"Elizabeth Rice-Reynolds","orcid":null,"position":1,"is_corresponding":false},{"id":1118250,"name":"Ly Thi Huong Nguyen","orcid":"0000-0003-0567-2562","position":2,"is_corresponding":false},{"id":333428,"name":"Anna Wood","orcid":"0000-0001-9533-3649","position":3,"is_corresponding":false},{"id":1092646,"name":"Cameron Cordero","orcid":"0000-0001-8320-0953","position":4,"is_corresponding":false},{"id":772624,"name":"Nicholas J. Bray","orcid":"0000-0002-4357-574X","position":5,"is_corresponding":false},{"id":1162730,"name":"Victoria Harcy","orcid":null,"position":6,"is_corresponding":false},{"id":768609,"name":"Rudri K Vyas","orcid":null,"position":7,"is_corresponding":false},{"id":768059,"name":"Debra Mitchell","orcid":"0000-0002-9343-075X","position":8,"is_corresponding":false},{"id":464108,"name":"Kirill S. Lobachev","orcid":"0000-0002-5775-1679","position":9,"is_corresponding":false},{"id":13970,"name":"Steven A. Roberts","orcid":"0000-0002-3628-5808","position":10,"is_corresponding":false},{"id":610908,"name":"Tony M. Mertz","orcid":"0000-0002-9243-4062","position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":null,"created_at":"2026-07-19T01:18:37.743462Z","pmid":"37532520","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":[]}