Recognizing and repairing chromosome damage

DNA is highly chemically reactive; there are many agents that occur normally inside cells that react with DNA in a way that could change the sequence and/or structure of the genome, with potentially catastrophic consequences. In addition to their potential mutagenicity, DNA damage can block important processes such as DNA replication, which can potentially prevent cell proliferation. So it’s important that DNA damage is repaired rapidly to prevent mutations, rearrangements or changes in chromosome number from occurring.

We are interested in how cells detect, signal and repair DNA damage and how they deal with blocks to DNA replication. In the past years we have discovered a range of completely new proteins in mammalian cells that are instrumental for repair of DNA damage and broken replication forks. Some of these – such as SLX4 – are mutated in debilitating human diseases. We are interested in figuring out the modes of action of these proteins and their relevance to disease, and in discovering more new players in DNA repair. Many important chemotherapeutic agents act by inducing DNA damage and/or DNA replication stress and we are interested in finding ways of making these therapies more effective and in preventing resistance. Furthermore we are involved in identifying new anti-cancer drug targets in the DNA repair arena.

We are particularly interested in DNA inter–strand crosslinks (ICLs). These are formed when bifunctional agents covalently link the two strands in a double helix. ICLs are toxic lesions that prevent strand separation necessary for transcription and DNA replication. ICLs are caused by endogenous metabolites, and the major route for ICL repair appears to be initiated when DNA replisomes collide with ICLs. The repair of ICLs involves multiple DNA repair pathways, but how they are removed and DNA replication re-started is unclear. Failure to repaie ICLs in humans causes the inherited disease Fanconi anaemia characterised by developmental abnormalities, bone marrow failure and cancer predisposition.

Project 1: How does protein ubiquitylation promote ICL repair?
We have set up new assays to identify new DNA repair genes and this project involves using these assays to screen for new regulators of DNA repair. We have already identified some new candidates that need to be characterised in detail