{"doi":"10.1371/journal.pbio.3000464","title":"Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation","abstract":null,"journal":"PLOS Biology","year":2019,"id":595776,"datarank":0.586803450814222,"base_score":3.912023005428146,"endowment":3.912023005428146,"self_citation_contribution":0.586803450814222,"citation_network_contribution":0.0,"self_endowment_contribution":0.586803450814222,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":13996,"name":"Natalie Saini","orcid":"0000-0002-1668-5417","position":1,"is_corresponding":false},{"id":13666,"name":"Leszek J. Klimczak","orcid":"0000-0003-3048-2576","position":2,"is_corresponding":false},{"id":13332,"name":"Kin Chan","orcid":"0000-0002-5827-3154","position":3,"is_corresponding":false},{"id":108245,"name":"Ewa P. Malc","orcid":"0000-0002-4596-1142","position":4,"is_corresponding":false},{"id":13808,"name":"Piotr A. Mieczkowski","orcid":"0000-0003-2418-0096","position":5,"is_corresponding":false},{"id":1525762,"name":"Adam B. Burkholder","orcid":null,"position":6,"is_corresponding":false},{"id":1525763,"name":"David Fargo","orcid":null,"position":7,"is_corresponding":false},{"id":13498,"name":"Dmitry A. Gordenin","orcid":"0000-0002-8399-1836","position":8,"is_corresponding":false},{"id":483060,"name":"Cynthia J. Sakofsky","orcid":"0000-0002-0959-3688","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation","abstract":"A single cancer genome can harbor thousands of clustered mutations. Mutation signature analyses have revealed that the origin of clusters are lesions in long tracts of single-stranded (ss) DNA damaged by apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, raising questions about molecular mechanisms that generate long ssDNA vulnerable to hypermutation. Here, we show that ssDNA intermediates formed during the repair of gamma-induced bursts of double-strand breaks (DSBs) in the presence of APOBEC3A in yeast lead to multiple APOBEC-induced clusters similar to cancer. We identified three independent pathways enabling cluster formation associated with repairing bursts of DSBs: 5' to 3' bidirectional resection, unidirectional resection, and break-induced replication (BIR). Analysis of millions of mutations in APOBEC-hypermutated cancer genomes revealed that cancer tolerance to formation of hypermutable ssDNA is similar to yeast and that the predominant pattern of clustered mutagenesis is the same as in resection-defective yeast, suggesting that cluster formation in cancers is driven by a BIR-like mechanism. The phenomenon of genome-wide burst of clustered mutagenesis revealed by our study can play an important role in generating somatic hypermutation in cancers as well as in noncancerous cells.","is_dataset_classified":null,"base_score":3.912023005428146,"endowment":3.912023005428146,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31568516","pmcid":"PMC6786661","openalex_id":"https://openalex.org/W2976483929","authors":[],"funders":[{"funder_name":"US National Institute of Health Intramural Research Program","grant_id":"Z1AES103266","title":null},{"funder_name":"NIEHS NIH HHS","grant_id":"ZIA ES103266","title":null}],"total_grants":2,"fwci":2.4276,"citation_percentile":0.90189277,"influential_citations":0,"citation_trend":[{"year":2020,"count":15},{"year":2021,"count":8},{"year":2022,"count":9},{"year":2023,"count":4},{"year":2024,"count":6},{"year":2025,"count":5},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1371/journal.pbio.3000464","host_type":"journal"},{"url":"https://doi.org/10.1371/journal.pbio.3000464","host_type":"publisher"},{"url":"http://dx.plos.org/10.1371/journal.pbio.3000464","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31568516","host_type":"repository"},{"url":"https://pubmed.ncbi.nlm.nih.gov/32142506","host_type":"repository"},{"url":"https://doaj.org/article/d6c7a133727a467599ef6850e49ee96e","host_type":"repository"},{"url":"https://figshare.com/articles/dataset/Repair_of_multiple_simultaneous_double-strand_breaks_causes_bursts_of_genome-wide_clustered_hypermutation/9921836","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6786661","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7059901","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC6786661","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6786661?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["CRISPR and Genetic Engineering","DNA Repair Mechanisms","RNA Research and Splicing","APOBEC Deaminases","DNA Breaks, Double-Stranded","Gamma Rays","Genome, Fungal","Humans","Mutagenesis","Neoplasms","Saccharomyces cerevisiae"],"mesh_terms":["APOBEC Deaminases","Gamma Rays","Humans","Neoplasms","Saccharomyces cerevisiae","Mutagenesis","Genome, Fungal","DNA Breaks, Double-Stranded"],"keywords":["APOBEC","Somatic hypermutation","Biology","Mutagenesis","Genetics","Genome","Mutation","DNA repair","DNA","Molecular biology","Gene"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"dbgap"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-27T17:52:48.863922Z","pmid":null,"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":[]}