Regulation of E2 Promoter Binding Factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37 [Signal Transduction]

September 22nd, 2015 by Mahanic, C. S., Budhavarapu, V., Graves, J. D., Li, G., Lin, W.-C.

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 K63-linked ubiquitination of E2F1 and activates its transcriptional activity. UCH37 depletion reduces 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 expressions of E2F1 proliferative and pro-apoptotic genes are correlated with the levels of UCH37 in many primary tumors. These results uncover a novel mechanism for E2F1 transcriptional activation through removal of its K63-linked ubiquitination by UCH37.