{"doi":"10.17615/ekwn-0a54","title":"The human decatenation checkpoint","abstract":"Chromatid catenation is actively monitored in human cells, with progression from G2 to mitosis being inhibited when chromatids are insufficiently decatenated. Mitotic delay was quantified in normal and checkpoint-deficient human cells during treatment with ICRF-193, a topoisomerase II catalytic inhibitor that prevents chromatid decatenation without producing topoisomerase-associated DNA strand breaks. Ataxia telangiectasia (A-T) cells, defective in DNA damage checkpoints, showed normal mitotic delay when treated with ICRF-193. The mitotic delay in response to ICRF-193 was ablated in human fibroblasts expressing an ataxia telangiectasia mutated- and rad3-related (ATR) kinase-inactive ATR allele (ATRki). BRCA1-mutant HCC1937 cells also displayed a defect in ICRF-193-induced mitotic delay, which was corrected by expression of wild-type BRCA1. Phosphorylations of hCds1 or Chk1 and inhibition of Cdk1 kinase activity, which are elements of checkpoints associated with DNA damage or replication, did not occur during ICRF-193-induced mitotic delay. Over-expression of cyclin B1 containing a dominant nuclear localization signal, and inhibition of Crm1-mediated nuclear export, reversed ICRF-193-induced mitotic delay. In combination, these results imply that ATR and BRCA1 enforce the decatenation G2 checkpoint, which may act to exclude cyclin B1/Cdk1 complexes from the nucleus. Moreover, induction of ATRki produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability.","journal":"UNC Libraries","year":2021,"id":230787,"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":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":837172,"name":"Paul R. Graves","orcid":"0000-0002-4958-7450","position":1,"is_corresponding":false},{"id":62849,"name":"Helen Piwnica‐Worms","orcid":"0000-0003-4210-6738","position":2,"is_corresponding":false},{"id":82106,"name":"Charlotte Downes","orcid":null,"position":3,"is_corresponding":false},{"id":65889,"name":"Richard S. Paules","orcid":"0000-0001-9106-7486","position":4,"is_corresponding":false},{"id":439393,"name":"Hui Zhao","orcid":"0000-0001-8160-6415","position":5,"is_corresponding":false},{"id":837669,"name":"Cheryl A. Cistulli","orcid":null,"position":6,"is_corresponding":false},{"id":666494,"name":"Paula B. Deming","orcid":"0000-0003-3278-1705","position":7,"is_corresponding":false},{"id":437125,"name":"William K. Kaufmann","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:09.211909Z","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":[]}