{"doi":"10.1016/j.celrep.2020.01.020","title":"A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability","abstract":"The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation.","journal":"Cell Reports","year":2020,"id":91320,"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":45,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":436438,"name":"Dennis A. Simpson","orcid":"0000-0001-5332-8243","position":1,"is_corresponding":false},{"id":457306,"name":"Rashmi J. Kumar","orcid":"0000-0002-8742-2753","position":2,"is_corresponding":false},{"id":86811,"name":"Luciano G. Martelotto","orcid":"0000-0002-9625-1183","position":3,"is_corresponding":false},{"id":408412,"name":"Lisle E. Mose","orcid":null,"position":4,"is_corresponding":false},{"id":457307,"name":"Naim U. Rashid","orcid":"0000-0002-7274-8259","position":5,"is_corresponding":false},{"id":457308,"name":"Alice Y. Ho","orcid":"0000-0002-6812-4187","position":6,"is_corresponding":false},{"id":236124,"name":"Simon N. Powell","orcid":"0000-0002-8183-4765","position":7,"is_corresponding":false},{"id":458182,"name":"Yuetao Wen","orcid":null,"position":8,"is_corresponding":false},{"id":13902,"name":"Joel S. Parker","orcid":"0000-0003-2080-6901","position":9,"is_corresponding":false},{"id":14428,"name":"Jorge S. Reis‐Filho","orcid":"0000-0003-2969-3173","position":10,"is_corresponding":false},{"id":247634,"name":"John H.J. Petrini","orcid":"0000-0001-5102-5679","position":11,"is_corresponding":false},{"id":457309,"name":"Gaorav P. Gupta","orcid":"0000-0001-9177-552X","position":12,"is_corresponding":false},{"id":458181,"name":"Katerina D. Fagan‐Solis","orcid":null,"position":0,"is_corresponding":true}],"reference_count":82,"raw_metadata":null,"created_at":"2026-07-18T22:28:45.409789Z","pmid":"32023457","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":[]}