Walking the fine line of atypical E2F regulation during cell division

Abstract

The cell cycle is a series of events that take place in a cell leading to duplication of its DNA and division into two daughter cells. It is an extremely vital process that, is tightly controlled by an evolutionally conserved regulatory network. Among the regulatory pathways that control cell cycle, Rb-E2F signaling plays an important role to manipulate the expression of key cell cycle genes. Therefore, regulation of the Rb-E2F pathway activity is essential to control the cell cycle, and its importance was illustrated by the fact that Rb is among the most frequently mutated genes in cancer cells, leading to increased E2F-mediated transcriptional activity that drives unscheduled proliferation. To date, a total of eight E2F transcription factors have been identified. Notably, E2F7 and E2F8 are “atypical” members of the E2F family for their Rb-independent repressor function and a distinctive mechanism to control gene expression. Atypical E2Fs are known to inhibit a network of genes involved in DNA replication, DNA metabolism, and DNA repair. However, how the activity of atypical E2Fs is controlled in normal cells and cancer cells, was largely unexplored. The studies from this thesis shine a clear light on this matter. We described two proteasomal degradation routes of atypical E2F in G1 and G2, by APC/CCdh1 (anaphase-promoting complex/cyclosome and Cdh1 subunit) and SCFcyclin F (Skp1-Cullin-F-box protein complex and cyclin F), respectively. We proved that these precise and timely regulations of atypical E2Fs are critical for proper cell cycle progression and DNA repair function. In addition, we found that repressor function of atypical E2F could be temporarily attenuated by Chk1 (Checkpoint kinase 1) and 14-3-3 proteins in response to DNA damage. This interplay sustains E2F-mediated transcription to avoid permanent cell death. Importantly, we observed a strong correlation between elevated levels of 14-3-3 proteins and E2F7/8 target gene expression in multiple types of cancers, suggesting that repressor functions of E2F7/8 were compromised to promote uncontrolled cell proliferation. Taken together, this thesis provides novel insight into the regulation of atypical E2Fs, and improved our understanding of cell cycle progression and DNA damage response.