{"doi":"10.1101/2023.10.03.560768","title":"The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5","abstract":"Summary Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, Cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 to promote cells progressing through the G1/S transition. However, the mechanisms underlying this second pathway are unknown. Here, we found that Rb’s concentration drop in G1 and recovery in S/G2 is controlled by phosphorylation-dependent protein degradation. In early G1 phase, un- and hypo-phosphorylated Rb is targeted by the E3 ligase UBR5. UBR5 knockout cells have higher Rb concentrations in early G1, exhibit a lower G1/S transition rate, and are more sensitive to Cdk4/6 inhibition. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391514,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9484,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1045274,"name":"Lucas Fuentes Valenzuela","orcid":"0009-0002-7403-3537","position":1,"is_corresponding":false},{"id":250300,"name":"Evgeny Zatulovskiy","orcid":"0000-0002-7847-5829","position":2,"is_corresponding":false},{"id":489938,"name":"Lise Mangiante","orcid":"0000-0001-8309-0950","position":3,"is_corresponding":false},{"id":255975,"name":"Christina Curtis","orcid":"0000-0003-0166-3802","position":4,"is_corresponding":false},{"id":250304,"name":"Jan M. Skotheim","orcid":"0000-0001-8420-6820","position":5,"is_corresponding":false},{"id":250301,"name":"Shuyuan Zhang","orcid":"0000-0002-6220-5998","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-19T01:18:47.408273Z","pmid":"37873473","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":[]}