Research

Transcriptional stress — for example caused by DNA lesions in active genes or by inhibition of elongation — produces discrete signalling events that recruit checkpoint factors and can rapidly stabilise/activate p53. We investigate the molecular intermediates (RPA, ATR and associated factors) that link stalled transcription complexes to canonical DNA damage checkpoint pathways and p53 modification, nuclear localisation and transcriptional responses.

By combining inducible locus-specific damage systems with genomic run-on assays, chromatin immunoprecipitation and proteomics, we map events from polymerase stalling to checkpoint kinase activation and the p53-dependent transcriptional programme that determines cell-cycle arrest, apoptosis or survival.

Using defined double-strand breaks in model promoter CpG islands, we have shown that chromatin silencers including SIRT1, polycomb members and DNA methyltransferases can be recruited to damaged loci and — under some circumstances — initiate CpG methylation and persistent silencing. Current work examines how repair pathway choice, local chromatin state and interacting repair proteins determine the probability of a transient damage event producing a stable epigenetic change.

We are particularly interested in interactions between repair proteins (for example mismatch repair factors) and DNMT recruitment after oxidative damage, and how inflammatory signals or repeated lesions bias outcomes toward heritable methylation changes during tumour initiation.

Chronic inflammation produces reactive species that damage DNA and alter chromatin. Our work dissects the cascade from inflammation-mediated damage to recruitment of mismatch-repair proteins (for example MSH2-MSH6), subsequent DNMT1 recruitment and local transcriptional repression. We test these mechanisms in inflammation-driven mouse models of colon tumourigenesis and in human tissue models.

We also study metabolic and mitochondrial consequences of inflammation-induced epigenetic change that can reshape tumour metabolic programmes, and we investigate how these changes interact with oncogenic signalling (for example mutant BRAF) to promote cell plasticity and tumour progression.

Standard chemotherapies and targeted agents can provoke epigenetic responses that select for or generate therapy-tolerant persister cells. We investigate how histone modifiers (for example LSD1), DNA methylation and polycomb activity cooperate with oncogenic signalling to stabilise alternative transcriptional programmes and permit lineage plasticity in colorectal and ovarian cancer models.

Our translational goal is to identify chromatin vulnerabilities — enzymes or cofactors — whose inhibition prevents the emergence or maintenance of resistant cell states and improves responses when combined with standard therapies.