E2Fs

E2Fs are a family of transcription factors that regulate cell cycle progression and DNA synthesis. They form heterodimers with DP proteins to bind DNA at E2F-regulated promoters and drive expression of genes required for S-phase entry. Their activity is tightly controlled by the RB family of pocket proteins, linking cell cycle progression to cellular growth status.

In humans, the E2F family includes eight members. E2F1, E2F2, and E2F3 can act as transcriptional activators; E2F3 has two isoforms, E2F3a and E2F3b, with E2F3a mainly activating transcription and E2F3b acting as a repressor. The remaining E2Fs—E2F4, E2F5, E2F6, E2F7, and E2F8—primarily function as repressors in many contexts, with E2F7 and E2F8 capable of DP-independent repression. DP1 and DP2 are the principal dimerization partners for most E2Fs.

E2F target genes include those required for DNA replication, nucleotide metabolism, and cell cycle progression, such as Cyclin E, Cyclin A, PCNA, MCMs, and DNA polymerases. In G1, hypophosphorylated RB binds E2F and represses transcription; phosphorylation by cyclin-CDK complexes releases E2F to activate gene expression and promote S-phase entry. E2F1, in particular, can also promote apoptosis in response to DNA damage, linking cell cycle control to cell fate decisions. Viral oncoproteins like HPV E7 and SV40 large T antigen disrupt RB-E2F control to stimulate proliferation.

Regulation extends to chromatin modifiers and post-translational modifications; misregulation of E2Fs is associated with developmental defects and cancer, where E2F activity is often increased or deregulated. Overall, E2Fs serve as a central regulatory node that integrates growth signals with DNA synthesis and cell fate, balancing proliferation and quiescence in normal development and disease.