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., UV, radiation, chemicals) and from normal processes of cell growth (e.g., metabolic byproducts, DNA replication, transcription).
We are particularly interested in the regulation of homologous recombination (HR), which is essentially catalysed by the evolutionarily highly conserved recombinase, Rad51. HR normally takes place during S and G2 phases of the cell cycle and provides a mechanism for the faithful recovery of the missing genomic information by using the replicated sister DNA as a template, ensuring genome stability. However, if HR is active throughout the cell cycle and uses a similar but non-identical DNA as a template, regions of genomic DNA can be amplified, deleted or exchanged, resulting in genome instability.
Our primary research question is: how is HR activated at the right time and at the right location in human cells? Genome size has increased enormously during evolution, and the set of genes that regulate HR has evolved in line with this increased complexity. In humans, mutations of these genes contribute to the development of various genome instability syndromes. BRCA2 (breast cancer, 2) and PALB2 (partner and localiser of BRCA2), also known as FANCD1 (Fanconi anaemia, type D1) and FANCN (Fanconi anaemia, type N), respectively, form a complex with Rad51 and play a vital role in the regulation of HR. Interestingly, our group has found that central cell cycle drivers cyclin-dependent kinases (CDKs) and polo-like kinase 1 phosphorylate this BRCA-complex and also play important roles in fine-tuning HR. We aim to obtain a more complete picture of this regulatory mechanism in both perturbed and unperturbed human cells using a multidisciplinary approach that includes molecular and cellular biology, biochemistry, proteomics and genome-wide ChIP-seq.
Cell Rep 7: 1547-59.
Mol. Cell 45: 371-83.
Nature Struc Mol Biol. 14: 468-474
Nature (Article) 434: 598-604