During my PhD I am investigating the role that E2F-dependent cell cycle transcription plays during the DNA replication stress checkpoint response in mammalian cells. DNA replication stress is defined as the slowing down or stalling of DNA replication forks; this can cause DNA damage and subsequent genome instability. To prevent this cells have evolved a cellular response called the DNA replication stress checkpoint. As oncogene-induced replication stress is an early event in tumourigenesis, understanding this checkpoint may give insight into how to target this response to specifically generate replication stress-induced DNA damage in cancer cells. This could be used in combination with strategies exploiting the frequently compromised DNA repair and damage response in cancers for anti-cancer treatments. Our lab has previously shown that the DNA replication stress checkpoint response maintains E2F-dependent cell cycle transcription through Chk1 phosphorylating and inhibiting the transcriptional repressor E2F6. However, the role and importance of transcription in the cellular response to replication stress remains largely unknown. My work, and that of others in the lab, has shown that in mammalian cells, unlike yeast, active protein synthesis is required for an efficient checkpoint response. Specifically, our work shows that many essential functions of the checkpoint response, including fork stalling, stabilisation and resolution, are compromised when sustained E2F-dependent transcription is impaired. We find that E2F-dependent transcription is also required during oncogene-induced replication stress to prevent replication stress-induced DNA damage and cell death. In the context of oncogene-induced replication stress the increased reliance on sustained E2F-dependent transcription creates a potentially large therapeutic window for damaging cancer cells without affecting normal cells. During the remainder of my PhD I am investigating the mechanism of E2F6-dependent repression with the aim of understanding the importance of cancer-associated mutations in E2F6 more clearly.