{"doi":"10.1101/2025.06.18.660431","title":"Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma","abstract":"Abstract DNA damage from routine cellular processes or exogenous insults can have a lasting impact on gene regulation beyond genetic mutations. The prevailing paradigm for the consequences of DNA damage repair revolves around restoration of the original genetic sequence, but long-term changes in chromatin configuration, gene expression and DNA modifications have not been analyzed. We introduced numerous, simultaneous Cas9-mediated DNA double strand breaks (DSBs) at defined locations in human glioblastoma cells and tracked both non-genetic and genetic alterations over time. Megabase-scale genomic alterations that endured two weeks after the initial damage were detected, involving a shift from transiently increased intra-TAD interactions to persistent long range cis and trans contacts, alterations in gene-expression and associated large structural variations. These findings reveal that widespread DNA damage, such as chemotherapy or radiotherapy, can trigger long-term genetic and non-genetic modifications which alter cellular function and may impact tumor outcome and the emergence of resistant cells.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":568968,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"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":1056362,"name":"Keerthivasan Raanin Chandradoss","orcid":"0000-0002-1990-0194","position":1,"is_corresponding":false},{"id":322441,"name":"Catherine Do","orcid":"0000-0002-9796-4345","position":2,"is_corresponding":false},{"id":945117,"name":"Ravesanker Ezhilarasan","orcid":"0000-0002-1353-8307","position":3,"is_corresponding":false},{"id":631315,"name":"Theodore Sakellaropoulos","orcid":null,"position":4,"is_corresponding":false},{"id":1257273,"name":"Jerome M. Karp","orcid":"0000-0001-7266-0946","position":5,"is_corresponding":false},{"id":945118,"name":"Yingwen Ding","orcid":"0000-0001-7673-8499","position":6,"is_corresponding":false},{"id":945119,"name":"Ze-Yan Zhang","orcid":"0000-0002-7896-3013","position":7,"is_corresponding":false},{"id":1257746,"name":"Melanie Graciani","orcid":null,"position":8,"is_corresponding":false},{"id":1327859,"name":"Giulia Cova","orcid":"0000-0001-6489-8807","position":9,"is_corresponding":false},{"id":401458,"name":"Jennifer E. Phillips‐Cremins","orcid":"0000-0002-4702-0450","position":10,"is_corresponding":false},{"id":275936,"name":"Erik P. Sulman","orcid":"0000-0003-4933-9120","position":11,"is_corresponding":false},{"id":238127,"name":"Jane A. Skok","orcid":"0000-0002-4145-1516","position":12,"is_corresponding":false},{"id":304305,"name":"Aram S. Modrek","orcid":"0000-0001-7586-9833","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:56:55.795846Z","pmid":"40667295","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":[]}