{"doi":"10.7554/elife.79570","title":"Variation in ubiquitin system genes creates substrate-specific effects on proteasomal protein degradation","abstract":"Precise control of protein degradation is critical for life, yet how natural genetic variation affects this essential process is largely unknown. Here, we developed a statistically powerful mapping approach to characterize how genetic variation affects protein degradation by the ubiquitin-proteasome system (UPS). Using the yeast Saccharomyces cerevisiae , we systematically mapped genetic influences on the N-end rule, a UPS pathway in which protein N-terminal amino acids function as degradation-promoting signals. Across all 20 possible N-terminal amino acids, we identified 149 genomic loci that influence UPS activity, many of which had pathway- or substrate-specific effects. Fine-mapping of four loci identified multiple causal variants in each of four ubiquitin system genes whose products process ( NTA1 ), recognize ( UBR1 and DOA10 ), and ubiquitinate ( UBC6 ) cellular proteins. A cis -acting promoter variant that modulates UPS activity by altering UBR1 expression alters the abundance of 36 proteins without affecting levels of the corresponding mRNA transcripts. Our results reveal a complex genetic basis of variation in UPS activity.","journal":"eLife","year":2022,"id":264543,"datarank":0.4247826567436698,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.040040253124439186,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.040040253124439186,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":4,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.951,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE213689"]},"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":362562,"name":"Gemechu Mekonnen","orcid":null,"position":1,"is_corresponding":false},{"id":20925,"name":"Frank W. Albert","orcid":"0000-0002-1380-8063","position":2,"is_corresponding":false},{"id":366574,"name":"Mahlon Collins","orcid":"0000-0001-6799-5645","position":0,"is_corresponding":true}],"reference_count":122,"raw_metadata":null,"created_at":"2026-07-19T00:26:41.845195Z","pmid":"36218234","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":[]}