Research

Research Interests

My research interests lay primarily in the study of the DNA damage response (DDR) and the role that DNA repair mechanisms, in particular, protect against cancer. Specific areas of activity are the human genetic disorder Fanconi anaemia (eg: DOI: 10.1016/j.molcel.2010.03.003) and the role of the dinucleotide Ap4A in the DDR (eg: DOI: 10.1016/j.dnarep.2015.06.008).

Fanconi anaemia (FA) is characterised by bone marrow failure, genetic instability and cancer predisposition, particularly acute myeloid leukaemia (AML) and head and neck squamous cell carcinoma (HNSCC). At least twenty FA genes have now been identified and the encoded proteins operate in the DDR to interstrand cross-links (ICL). This form of damage, induced by agents such as mitomycin C and cis-platin, links the two strands of DNA and stalls the progression of DNA replication. It is now believed that the FA pathway protects cells from DNA damage arising from endogenous aldehydes such as acetaldehyde and formaldehyde. Several of the FA genes are also breast cancer susceptibility genes, most notably FANCD1/BRCA2. My research on FA has focused on the role of the proteins FANCG and FANCD2, in particular how phosphorylation modulates their activity and their protein binding partners (DOI: 10.1038/sj.onc.1211034), how they function in homologous recombination repair, potential roles they may have outside of the canonical FA pathway and how they predispose to a variety of cancers including breast and cervical cancer (DOI: 10.2353/ajpath.2010.090779).

The dinucleotide diadenosine tetraphosphate (Ap4A) is synthesised in response to a variety of stresses and has previously been implicated in DNA damage responses. We have established that Ap4A plays an important role in cellular responses to DNA damaging agents, in particular ICL agents such as mitomycin C, but also aldehydes including acetaldehyde. Research on Ap4A is focused on elucidating the role Ap4A plays in mediating cellular responses to ICL and in how Ap4A may down-regulate cancer promoting genes (DOI: 10.1371/journal.pone.0154674).