{"doi":"10.1101/2021.09.14.460335","title":"Cdc6 is sequentially regulated by PP2A-Cdc55, Cdc14 and Sic1 for origin licensing in <i>S. cerevisiae</i>","abstract":"Abstract Cdc6, a subunit of the pre-replicative complex, contains multiple regulatory Cdk1 consensus sites, SP or TP motifs. In S. cerevisiae , Cdk1 phosphorylates Cdc6-T7 to recruit Cks1, the Cdk1 phospho-adaptor in S-phase, for subsequent multisite phosphorylation and protein degradation. Cdc6 accumulates in mitosis and is tightly bound by Clb2 through N-terminal phosphorylation in order to prevent premature origin licensing and degradation. It has been extensively studied how Cdc6 phosphorylation is regulated by the Cyclin-Cdk1 complex. However, a detailed mechanism on how Cdc6 phosphorylation is reversed by phosphatases has not been elucidated. Here, we show that PP2A Cdc55 dephosphorylates Cdc6 N-terminal sites to release Clb2. Cdc14 dephosphorylates the C-terminal phospho-degron, leading to Cdc6 stabilization in mitosis. In addition, the Cdk1 inhibitor, Sic1, releases Clb2·Cdk1·Cks1 from Cdc6 to load Mcm2-7 on the chromatin upon mitotic exit. Thus, pre-RC assembly and origin licensing is promoted by the attenuation of distinct CDK-dependent Cdc6 inhibitory mechanisms.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226613,"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":0.9528,"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":395204,"name":"Mihkel Örd","orcid":"0000-0003-0454-7241","position":1,"is_corresponding":false},{"id":830492,"name":"Andriele Silva","orcid":null,"position":2,"is_corresponding":false},{"id":707739,"name":"Shaneen Singh","orcid":"0000-0002-4003-5756","position":3,"is_corresponding":false},{"id":609024,"name":"John F.X. Diffley","orcid":"0000-0001-5184-7680","position":4,"is_corresponding":false},{"id":609023,"name":"Dirk Remus","orcid":"0000-0002-5155-181X","position":5,"is_corresponding":false},{"id":395207,"name":"Mart Loog","orcid":"0000-0003-1330-8453","position":6,"is_corresponding":false},{"id":451164,"name":"Amy E. Ikui","orcid":"0000-0002-2712-5351","position":7,"is_corresponding":false},{"id":829978,"name":"Jasmin Philip","orcid":"0000-0001-9030-9228","position":0,"is_corresponding":true}],"reference_count":114,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:38.004707Z","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":[]}