Replication stress, or replication-associated DNA damage, occurs frequently in cancer. There is a growing interest in targeting oncogene-induced replication stress for cancer therapy. Effective targeting will require mechanistic understanding of how oncogenes induce replication stress.
It is widely appreciated that oncogenes can promote replication stress by de-regulating the cell cycle machinery to increase proliferation. To promote proliferation, oncogenes also need to hyper-activate the basal transcription machinery. We have evidence for transcription hyper-activation as an alternative and important replication stress mechanism. We recently reported that H-RASV12 induces replication-transcription conflicts, not by de-regulating the cell cycle, but by increasing global RNA synthesis and the accumulation of RNA-DNA hybrids (R-loops).
This project will further investigate the mechanisms and importance of RNA-DNA hybrid accumulation and transcription-replication conflicts in colorectal cancer models, and how these processes may affect response to cancer therapy.
Methods: Cancer cell culture, cancer models, organoids, molecular biology, siRNA, lentivirus, microscopy, cell growth and survival, DNA replication assays, DNA damage and repair assays, cancer therapy
Lab website: https://www.evapetermann.org/