Abstract A105: Checkpoint kinase 1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest

Abstract

Abstract The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes, providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that E2F7 and E2F8 can be directly phosphorylated by Checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that multiple 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. We show that 14-3-3 proteins inhibit E2F7 and E2F8 repressor function without disrupting their binding to target gene promoters or subcellular translocation. In addition, we observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2Fs target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to replication stress and DNA-damaging therapeutic reagents, which are both known inducers of Chk1 activity. Citation Format: Ruixue Yuan. Checkpoint kinase 1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A105.