Research

Transcription-replication conflicts in cancer

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. However to promote proliferation, oncogenes also need to hyper-activate the basal transcription machinery. We use DNA fibre approaches to identify new mechanisms of oncogene-induced replication stress.

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 expression of a general transcription factor (TBP) and global RNA synthesis. We showed that TBP overexpression can promote replication stress independently of oncogenes.

We are further investigating the mechanisms of oncogene-induced transcription-replication conflicts. We are also investigating transcription-replication conflicts induced by a new class of cancer drugs called BET inhibitors.

BET inhibitor project

H-Ras project

Cyclin E project

Homologous recombination at stalled replication forks

Homologous recombination (HR) is a remarkable genome maintenance pathway that brings together DNA replication and DNA repair. Because of this, it is absolutely central to diseases characterized by replication stress or treated with replication stress-inducing agents.

It is increasingly evident that HR processes frequently occur at perturbed replication forks, where HR performs novel roles that are distinct from its classic function in DNA double-strand break repair. New insights into the roles of HR at stressed replication forks are relevant for cancer development and therapy. We are particularly interested in understanding how HR can slow and stall forks.

We use DNA fibre approaches to identify new roles for HR and the central HR factor RAD51 at stalled replication forks. We study how RAD51 modulates fork progression in response to classic chemotherapy, targeted cancer therapies, and environmental mutagens.

BPDE PrimPol project

Gemcitabine project


Transcription-replication conflicts visualised in the lab... Definitely one of our methods!