{"doi":"10.1093/hmg/ddt133","title":"Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle","abstract":null,"journal":"Human Molecular Genetics","year":2013,"id":668143,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":630136,"name":"Kazunori Tomita","orcid":"0000-0003-1096-6725","position":1,"is_corresponding":false},{"id":1744755,"name":"Alexander Booth","orcid":null,"position":2,"is_corresponding":false},{"id":1744756,"name":"Joshua Poznansky","orcid":null,"position":3,"is_corresponding":false},{"id":1576351,"name":"Andrew C.G. Porter","orcid":null,"position":4,"is_corresponding":false},{"id":1744754,"name":"Polly Gravells","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle","abstract":"Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. Cdk1 promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds. We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in Cdk1 activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid Cdk1 activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a Cdk1 inhibitors.","is_dataset_classified":null,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23525902","pmcid":null,"openalex_id":"https://openalex.org/W2100068257","authors":[],"funders":[{"funder_name":"Cancer Research UK","grant_id":"12097","title":null},{"funder_name":"Biotechnology and Biological Sciences Research Council","grant_id":"BB/H003371/1","title":"Cell cycle control of DNA double strand break repair and the role of Cdk"},{"funder_name":"European Commission","grant_id":"281722","title":"Hidden role of the meiotic chromosomal bouquet"}],"total_grants":3,"fwci":0.5502,"citation_percentile":0.66782377,"influential_citations":0,"citation_trend":[{"year":2014,"count":1},{"year":2015,"count":2},{"year":2016,"count":1},{"year":2019,"count":2},{"year":2021,"count":2},{"year":2024,"count":1},{"year":2025,"count":1}],"oa_status":"closed","license":null,"oa_locations":[{"url":"http://academic.oup.com/hmg/article-pdf/22/14/2842/17259284/ddt133.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/hmg/ddt133","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23525902","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1013.9576","host_type":""},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.1026.5648","host_type":""},{"url":"https://discovery.ucl.ac.uk/id/eprint/1393786/","host_type":"repository"},{"url":"https://academic.oup.com/hmg/article-pdf/22/14/2842/17259284/ddt133.pdf","host_type":""},{"url":"http://dx.doi.org/10.1093/hmg/ddt133","host_type":""},{"url":"https://dx.doi.org/10.1093/hmg/ddt133","host_type":""},{"url":"https://discovery-pp.ucl.ac.uk/id/eprint/1393786/","host_type":""}],"fields_of_study":["DNA Repair Mechanisms","Cancer-related Molecular Pathways","Microtubule and mitosis dynamics","0301 basic medicine","0303 health sciences","03 medical and health sciences","Animals","CDC2 Protein Kinase","Cell Cycle","Cell Cycle Proteins","Cell Division","Cell Line, Tumor","Cell Proliferation","Cell Survival","G2 Phase","Humans","Mitosis","Protein Kinases","Pyrazoles","Pyrimidines","Xenopus","Xenopus Proteins"],"mesh_terms":["Animals","Cell Cycle","Cell Division","Cell Survival","Humans","Mitosis","Protein Kinases","Pyrazoles","Pyrimidines","Xenopus","G2 Phase","CDC2 Protein Kinase","Cell Cycle Proteins","Xenopus Proteins","Cell Line, Tumor","Cell Proliferation"],"keywords":["Endoreduplication","Cyclin-dependent kinase 1","Biology","Mitosis","Cell cycle","Cell biology","Cell growth","Cell division","Kinase","Genetics","Cell","G2 Phase","Tumor","Cell Survival","Xenopus","Cell Cycle Proteins","Xenopus Proteins","Cell Line","Pyrimidines","Cell Line, Tumor","CDC2 Protein Kinase","Animals","Humans","Pyrazoles","Protein Kinases","Cell Proliferation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T20:17:23.973547Z","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":[]}