Atypical E2Fs: new players in the E2F transcription factor family

Abstract

As major regulators of the cell cycle, apoptosis and differentiation, E2F transcription factors have been studied extensively in a broad range of organisms. The recent identification of atypical E2F family members further expands our structural, functional and molecular view of the cellular E2F activity. Unlike other family members, atypical E2Fs have a duplicated DNA-binding domain and control gene expression without heterodimerization with dimerization partner proteins. Recently, knockout strategies in plants and mammals have pinpointed that atypical E2Fs have a crucial role in plant cell size control, endocycle regulation, proliferation and apoptotic response upon DNA stress. Their position at the crossroads of proliferation and DNA stress response marks these novel E2F proteins as interesting study objects in the field of tumor biology.

Figure 1. Schematic representation of the E2F proteins and their three-dimensional structures

(a) The E2F protein family and DP proteins, and their structural organization and interaction regions with DNA and binding partners. The most peculiar differences are shown between classical E2Fs, DP proteins and atypical E2Fs, To indicate that the DBD1 of the atypical E2F resembles most that of the classical E2F, they have been given the same color (blue) as well as for DBD2 and that of the DP (red). In this general schematic representation, no difference in length, domain positions and other functional domains is indicated. (b) Structure of the E2F4/DP2 heterodimer with E2F4 (blue) and DP2 (red) bound to an E2F DNA consensus sequence (Protein Data Bank code 1CF7). Structural models based on homology modeling with the solved E2F4/DP2structure depicting the interaction between DBD1 (blue) and DBD2 (red) of E2F7 or E2Fe/DEL1. The putative DBDs of the E2F7 and E2Fe/DEL1 were aligned with the E2F4 and DP2 DBDs using the ClustalW program. Modeling requests were submitted to the SWISS-MODEL protein modeling server with the previously solved E2F4/DP2 crystal structure 1CF7 as the template. DBD, DNA-binding domain; DD, dimerization domain

Figure 2

Overview of the atypical E2F functions. Dashed lines mark biological links that are not fully supported yet by experimental data. Arrows indicate positive effects; bars represent repressive paths. Until now, no functional data for E2Fd/DEL2 has been reported. The observed cell elongation and upregulated expression of expansin genes in E2Ff/DEL3 knock-down plants positions this atypical E2F in the control of cell wall loosening. E2Fe/DEL1 levels have been reported to control the onset of endoreduplication through the transcriptional control of CCS52A2, an APC/C activator gene related to the mammalian CDH1 gene. Both CCS52A2 and CDH1 have previously been implicated in the regulation of endoreduplication. E2F7/E2F8 have been observed to bind the CDH1 promoter; whether or not this has a functional consequence remains to be determined. Additional E2F7/E2F8 target genes include E2F1, minichromosome maintenance (MCM) genes and cell division cycle 6 (CDC6). Whereas the transcriptional upregulation of E2F1 contributes to the observed apoptosis phenotype in E2f7/E2f8 double knockout embryos, the MCM and CDC6 targets reveal a role for atypical E2Fs in controlling cell proliferation. Importantly, the atypical E2F7/E2F8 themselves are E2F1 targets, generating a negative feedback loop. Whether this also is the case for the plant E2F/DEL proteins remains to be demonstrated.