title: Regulation of E2 promoter binding factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37.
abstract: E2F1 is tightly controlled by multiple mechanisms, but whether ubiquitination regulates its transcriptional activity remains unknown. Here we identify UCH37 as the first, to our knowledge, deubiquitinating enzyme for E2F1. UCH37 does not deubiquitinate UbK48 chains or affect E2F1 protein stability. Instead, UCH37, but not a catalytically dead mutant, decreases the Lys-63-linked ubiquitination of E2F1 and activates its transcriptional activity. UCH37 depletion reduces the gene expression of both proliferative and pro-apoptotic E2F1 target genes. UCH37 depletion also decreases both cell proliferation and apoptosis induction in functional assays. Interestingly, UCH37 expression is induced by E2F1, and its level rises in G1/S transition and S phase, suggesting a positive feedback loop between UCH37 and E2F1. UCH37 protein and mRNA levels are also induced after DNA damage. UCH37 localizes to the promoters of E2F1 pro-apoptotic target genes such as caspase 3, caspase 7, PARP1, and Apaf-1 and activates their expression after DNA damage. Moreover, the expression of E2F1 proliferative and pro-apoptotic genes is correlated with the levels of UCH37 in many primary tumors. These results uncover a novel mechanism for E2F1 transcriptional activation through removal of its Lys-63-linked ubiquitination by UCH37.
authors.affiliation: From the Section of Hematology/Oncology and Integrative Molecular and Biomedical Sciences Graduate Program, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Mahanic
authors.affiliation: From the Section of Hematology/Oncology and.
authors.forename: Varija
authors.initials: V
authors.lastname: Budhavarapu
authors.affiliation: From the Section of Hematology/Oncology and Integrative Molecular and Biomedical Sciences Graduate Program, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Graves
authors.affiliation: From the Section of Hematology/Oncology and.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: From the Section of Hematology/Oncology and Integrative Molecular and Biomedical Sciences Graduate Program, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030 weeichil@bcm.edu.
authors.forename: Weei-Chin
authors.initials: WC
authors.lastname: Lin
mesh_terms: D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000096:biosynthesis* / Q000235:genetics; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012333:RNA, Messenger; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase
keywords: DNA damage; E2F1; UCH37/UCHL5; apoptosis; deubiquitylation (deubiquitination); transcription regulation; ubiquitylation (ubiquitination)