Genome Stability and Cell Cycle
Our research goal is to elucidate how proliferating human cells safeguard their genomic DNA against various stresses coming from the environment (e.g., radiation, genotoxic agents) and from normal processes of cell growth (e.g., DNA replication, transcription & mitotic chromosome dynamics).
We are particularly interested in homologous recombination (HR), a repair mechanism which is catalysed by the evolutionarily conserved RecA-family recombinase RAD51. HR normally takes place during S and G2 phases of the cell cycle and, by using the replicated sister DNA as a repair template, can faithfully recover the missing genomic information. However, if HR wrongly uses a similar but non-allelic DNA as a repair template, regions of genomic DNA can be amplified, deleted or exchanged. Such non-allelic HR events could result in genome instability, but could conversely offer, in some situations, structural or functional robustness.
Genome size has increased enormously during evolution, with more than 50% of the human genome being repetitive. Reflecting this increased complexity, our genome encodes more recently evolved HR regulators, such as BRCA2 (breast cancer, 2) and PALB2 (partner and localiser of BRCA2). In humans, mutations of these HR regulators contribute to the development of various genome instability syndromes, including familial cancers and Fanconi anaemia, highlighting the importance of HR regulation.
We aim to understand how these HR regulators (e.g. BRCA2, PALB2 and beyond) coordinate their actions to control HR in the context of the cell cycle and at regions of genomic DNA that are prone to break or recombine. We take a multidisciplinary approach that includes molecular and cellular biology, genetics, biochemistry, proteomics and next-generation sequencing.
Nature Communications 12: 5380
EMBO Journal 39: e103002
Proc Natl Acad Sci U S A. 114: 7671-7676
Cell Rep 7: 1547-59
Mol. Cell 45: 371-83
EMBO Reports. 13: 35-41