Regulation of E2F1 by APC/C Cdh1 via K11 linkage-specific ubiquitin chain formation.

Cell Cycle
Varija N BudhavarapuWeei-Chin Lin

Abstract

E2F1 is a eukaryotic transcription factor that is known to regulate various cellular pathways such as cell cycle progression, DNA replication, DNA damage responses and induction of apoptosis. Given its versatile roles, a precise and tight regulation of E2F1 is very critical to maintain genomic stability. E2F1 is regulated both at transcriptional and posttranslational levels during cell cycle and upon DNA damage. After S phase, E2F1 is targeted for degradation and is kept at low levels or in an inactive state until the next G 1/S phase transition. Our studies show that APC/C ubiquitin ligase in conjunction with its co-activator Cdh1 (APC/C (Cdh1) ) can downregulate E2F1. We also identify an APC/C subunit APC5 that binds to E2F1 and is essential for E2F1 ubiquitination. We confirm an interaction between E2F1 and Cdh1 as well as an interaction between E2F1 and APC5 both in vivo and in vitro. In vitro GST pull-down assays have mapped the C-terminal 79 a.a. of E2F1 as Cdh1 interacting residues. Ectopically expressed Cdh1 downregulates the expression of E2F1-4. Our studies have also shown for the first time that E2F1 can be modified by K11-linkage specific ubiquitin chain formation (Ub-K11). The formation of Ub-K11 chains on E2F1 is ...Continue Reading

Citations

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