E2F7 represses a network of oscillating cell cycle genes to control S-phase progression

Abstract

E2F transcription factors are known to be important for timely activation of G 1 /S and G 2 /M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G 1 /S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resembles the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short-term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G 0 -G 1 /S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G 2 /M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G 1 /S genes during S-phase progression.