The TRIP-Br family of transcriptional regulators (TRIP-Br1 and TRIP-Br2) has been proposed to function at E2F-responsive promoters to integrate regulatory signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. To characterize the TRIP-Br "integrator" function(s), we have employed decoy peptides (*Br1 and *Br2) to antagonize the interaction between TRIP-Br1 or TRIP-Br2 and the PHD zinc finger and/or bromodomain of other transcription factors. Antagonism of the TRIP-Br integrator function elicits anti-proliferative effects through the transcriptional downregulation of a subset of E2F-responsive genes in vivo, and induces aberrant cyclin E accumulation, leading to Geminin deregulation and caspase-3-independent cellular sub-diploidization. The observed cyclin E deregulation is attributed to the downregulation of Fbxw7, which encodes the Fbw7 receptor subunit of the SCF(FBW7) ubiquitin ligase (E3) responsible for targeting cyclin E for proteolysis. Fbxw7 is identified herein as an E2F-responsive and TRIP-Br coregulated gene. Our results demonstrate a physiologic role for TRIP-Br in coupling E2F to novel functions in the regulation of cyclin E expression during cell cycle progression to ensure the proper execution of DNA replication and the maintenance of genomic stability.