{"doi":"10.1016/j.celrep.2021.110216","title":"ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization","abstract":"ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.","journal":"Cell Reports","year":2022,"id":235707,"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":76,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":303429,"name":"Brendan Mullan","orcid":null,"position":1,"is_corresponding":false},{"id":392870,"name":"Ramya Ravindran","orcid":"0000-0002-1058-5706","position":2,"is_corresponding":false},{"id":854601,"name":"Dana Messinger","orcid":"0000-0001-8421-0061","position":3,"is_corresponding":false},{"id":302157,"name":"Ruby Siada","orcid":"0000-0002-3088-9248","position":4,"is_corresponding":false},{"id":303428,"name":"Jessica Cummings","orcid":null,"position":5,"is_corresponding":false},{"id":854602,"name":"Micah Harris","orcid":"0000-0001-9919-5896","position":6,"is_corresponding":false},{"id":332764,"name":"Ashwath Muruganand","orcid":null,"position":7,"is_corresponding":false},{"id":854603,"name":"Kalyani Pyaram","orcid":"0000-0003-2744-7470","position":8,"is_corresponding":false},{"id":303426,"name":"Zachary Miklja","orcid":null,"position":9,"is_corresponding":false},{"id":855419,"name":"Mary Reiber","orcid":null,"position":10,"is_corresponding":false},{"id":303432,"name":"Taylor Garcia","orcid":null,"position":11,"is_corresponding":false},{"id":854604,"name":"Dustin Tran","orcid":"0000-0002-3715-5378","position":12,"is_corresponding":false},{"id":854605,"name":"Carla Danussi","orcid":"0000-0002-7474-1982","position":13,"is_corresponding":false},{"id":404986,"name":"Jacqueline A. 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