{"doi":"10.1093/narcan/zcaf052","title":"Targeted CRISPR knockout screening identifies known and novel chemogenomic interactions between DNA damaging agents and DNA repair genes","abstract":"Genetic instability is a hallmark of cancer, often arising from mutations to DNA damage repair and response (DDR) genes. Classical genetic, biochemical, and structural approaches elucidated the foundational mechanisms of DDR pathways and provided a scientific understanding of their involvement in repair of lesions induced by broad classes of DNA-damaging agents (DDAs). However, given the chemical diversity of DDAs and resultant DNA lesions, along with the multitude of interconnected DDR factors, the chemogenomic landscape of DDA-DDR interactions remains incompletely mapped. To this end, we developed a DDR-targeted, CRISPR knockout screening approach and assessed relationships amongst 353 DNA repair genes and 15 DDAs in LN229 glioma cells. Within this dataset of 5295 DDR-related chemogenomic interactions, we identified many established interactions and discovered novel ones. For example, we observed a specific role of transcription-coupled nucleotide excision repair in the repair of adducts generated by monofunctional alkylating agents, a role for the Fanconi anemia pathway in addressing methyl lesions, overt differences in DSB repair following treatment with topoisomerase I versus II poisons, and repair dependencies associated with the imidazotetrazines temozolomide, mitozolomide, and KL-50. Future directions will continue to investigate the mechanisms of novel chemogenomic interactions that we have uncovered as well as work to identify chemogenomic interactions amenable to clinical translation.","journal":"NAR Cancer","year":2025,"id":535939,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9482,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":257495,"name":"James L. Elia","orcid":"0000-0003-3962-7452","position":1,"is_corresponding":false},{"id":698088,"name":"Vijay Menon","orcid":"0000-0001-8009-5035","position":2,"is_corresponding":false},{"id":1420786,"name":"Spenser S. Johnson","orcid":null,"position":3,"is_corresponding":false},{"id":1420787,"name":"Sofia R. Arbelaez","orcid":null,"position":4,"is_corresponding":false},{"id":1283418,"name":"Sam Friedman","orcid":"0000-0003-1686-2791","position":5,"is_corresponding":false},{"id":1420788,"name":"Francesc Lopez-Giraldez","orcid":null,"position":6,"is_corresponding":false},{"id":657323,"name":"Ranjini K. Sundaram","orcid":"0000-0002-5725-0284","position":7,"is_corresponding":false},{"id":304471,"name":"Seth B. Herzon","orcid":"0000-0001-5940-9853","position":8,"is_corresponding":false},{"id":1420789,"name":"R BINDRA","orcid":null,"position":9,"is_corresponding":false},{"id":1278057,"name":"Susan E. Gueble","orcid":"0000-0002-8043-1147","position":10,"is_corresponding":false},{"id":552815,"name":"Collin D. Heer","orcid":"0000-0002-9005-3979","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41522810","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":[]}