Regulation of E2F1 Transcription Factor by Ubiquitin Conjugation

Abstract

Ubiquitination is a post-translational modification that defines the cellular fate of intracellular proteins. It can modify their stability, their activity, their subcellular location, and even their interacting pattern. This modification is a reversible event whose implementation is easy and fast. It contributes to the rapid adaptation of the cells to physiological intracellular variations and to intracellular or environmental stresses. E2F1 (E2 promoter binding factor 1) transcription factor is a potent cell cycle regulator. It displays contradictory functions able to regulate both cell proliferation and cell death. Its expression and activity are tightly regulated over the course of the cell cycle progression and in response to genotoxic stress. I discuss here the most recent evidence demonstrating the role of ubiquitination in E2F1's regulation.

Keywords: DNA damage; E2F1; cell cycle; ubiquitination.

Figure 1

Cell cycle regulation of E2F1 (E2 promotor binding factor 1) by ubiquitination. The E2F1 cellular content fluctuates along the cell cycle. It progressively increases in G1, peaks in S phase to promote the expression of genes required for the S-phase transition, then declines as cells progress through the S phase of the cell cycle. In G1, Rb (retinoblastoma) binds to E2F1 and represses its transcriptional activity. Sequestration of E2F1 by Rb stabilizes the protein and allows its accumulation during the G1 phase. The stability of E2F1 is controlled by ubiquitination throughout the cell cycle. In S phase, E2F1 is conjugated with K63-linked ubiquitin chains in a cIAP1 (cellular inhibitor of apoptosis 1)-dependent manner, contributing to its stabilization. At the end of the S phase, phosphorylation of E2F1 by CDK2 (cyclin-dependent kinase 2)/cyclin A complex is a signal for SCF (S-phase kinase-associated protein 1-cullinnn1-F-box)^skp2-mediated ubiquitination that targets E2F1 for proteasomal degradation. In the G2, M, and early G1 phases of the cell cycle, E2F1 content is maintained at low levels thanks to APC/C (anaphase promoting complex/cyclosome)^cdc20 and APC/C^cdh1-mediated ubiquitination and proteasomal degradation.

Figure 2

Schematic representation of E2F1 protein sequence (NP_005216.1). The regions interacting with cyclin A, Rb (retinoblastoma), and the E3-ubiquitine ligases skp2 (S-phase kinase-associated protein 2), cIAP1 (cellular inhibitor of apoptosis 1), and cdh1 are shown. Amino acid residues involved in post-translational modifications are indicated. E2F1 is subjected to several post-translation modifications in response to genotoxic stress, including phosphorylation on S³¹ by the ataxia telangiectasia mutated/ataxia telangiestasia and Rad3-related (ATM/ATR) [37], on S³⁶⁴ by checkpoint kinase 2 (chk2) [38], methylation on K¹⁸⁵ by Set7/9 [39,40], and on R¹⁰⁹ by the protein arginine N-methyltransferase 1 (PRMT1) [41], demethylation on R^111/113 [41], de-neddylation [42], and acetylation by the histone acetyl-transferase p300/CREB-binding protein-associated factor (P/CAF) on K^117/120/125 [43,44] and K63-ubiquitination on K^161/164 by cIAP1 [35]. The amino acid residues R^111/113 are targets of methylation by PRMT5 [41,45], K^117/120/125 of neddylation [46], K²⁶⁶ of sumoylation [47], S^332/337 of phosphorylation by the cyclin-dependent kinase 1 (cdk1) [48], and S⁴⁰³/T⁴³³ by the p38 mitogen-activated protein kinase (MAPK) [49]. DBD: DNA binding domain.