DNA replication is a fascinating and essential process.
Before dividing, a cell must rapidly and accurately replicate its entire genome. Defects in DNA replication can result in a range of defects (collectively termed ‘genome instability’), including mutation and chromosomal rearrangements; these underlie the genesis of cancer and other human diseases
DNA replication is intrinsically asymmetric. Only one parental strand at the replication fork can be continuously replicated: the other – the lagging strand – is discontinuously synthesized via the iterative polymerization, processing and ligation of Okazaki fragments. To fully replicate the human genome, a cell must synthesize and process around 20 million Okazaki fragments. We use a combined genetic and genomic approach to define how these intermediates are synthesized and processed in vivo.
We also use Okazaki fragments as a tool to study DNA replication dynamics in the cell. We seek to define what determines the sites of DNA replication initiation, and how the replication machinery overcomes the various obstacles it encounters in the genome.
We are also interested in DNA damage tolerance and repair, with a particular focus on ribonucleotide excision repair.
Before dividing, a cell must rapidly and accurately replicate its entire genome. Defects in DNA replication can result in a range of defects (collectively termed ‘genome instability’), including mutation and chromosomal rearrangements; these underlie the genesis of cancer and other human diseases
DNA replication is intrinsically asymmetric. Only one parental strand at the replication fork can be continuously replicated: the other – the lagging strand – is discontinuously synthesized via the iterative polymerization, processing and ligation of Okazaki fragments. To fully replicate the human genome, a cell must synthesize and process around 20 million Okazaki fragments. We use a combined genetic and genomic approach to define how these intermediates are synthesized and processed in vivo.
We also use Okazaki fragments as a tool to study DNA replication dynamics in the cell. We seek to define what determines the sites of DNA replication initiation, and how the replication machinery overcomes the various obstacles it encounters in the genome.
We are also interested in DNA damage tolerance and repair, with a particular focus on ribonucleotide excision repair.
Things we're currently working on include:
• What obstacles impede replisome movement in vivo?
How does the eukaryotic replisome move past (or through) obstacles?
What mechanisms lead to a loss of genome integrity around these sites?
• How do ribonucleotides mis-incorporated into genomic DNA affect cellular physiology, and how are they removed?
• What defines the site of replication initiation and termination in human and other eukaryotic cells?
• What obstacles impede replisome movement in vivo?
How does the eukaryotic replisome move past (or through) obstacles?
What mechanisms lead to a loss of genome integrity around these sites?
• How do ribonucleotides mis-incorporated into genomic DNA affect cellular physiology, and how are they removed?
• What defines the site of replication initiation and termination in human and other eukaryotic cells?