E2F transcription factors: master controllers of genomic integrity throughout the cell cycle

Abstract

In our body, hundreds of billions of cell divisions (mitoses) occur every day, and each mitosis must produce two daughter cells with identical genomic information. This is a highly controlled process to maintain tissue homeostasis. However, in cancers cell proliferation takes place in an uncontrolled manner, leading to malignant tumor formation. To discover better ways to treat cancer, it is of critical importance to understand the molecular mechanisms underlying cell division. In this dissertation, we studied the regulation and function of three E2F factors, that is E2F3, E2F7 and E2F8, during cell cycle. Particularly, in chapter 1, we introduce the roles of E2Fs people have found in regulation of cell cycle progression. In chapter 2, we reveal that E2F7 and -8 are subjected to SCFcyclin F-mediated degradation in G2 phase. In chapter 3, we then describe a noncanonical function of E2F7 and -8. We could show that E2F7 and -8 are required for this cohesin removal during prophase. In chapter 4 we switched our focus to the activating arm of the E2F family, and studied the role of E2F3 amplification, which is often seen in bladder cancer patients. We show in our bladder cancer cell lines that this E2F3-induced replication stress may sensitize cells to a class of drugs called intra-S-phase checkpoint inhibitors. Lastly, in chapter 5, we bring all these findings together and discuss the importance of coordinated regulation of E2F factors during cell cycle progression to preserve genome integrity.