Genome Replication Group
Dr Gideon Coster’s group investigates how cells produce accurate copies of their genome during cell division. Importantly, errors during genome replication can be both a cause, and a consequence, of cancer.
Research, projects and publications in this group
We hope to identify novel therapeutic approaches and potential drug targets by understanding the events that occur when the DNA replication machinery encounters challenging sequences in the genome.
Dr Gideon Coster
Group Leader:
Genome Replication
Dr Gideon Coster studies how errors during genome DNA replication are avoided or dealt with using a combination of in vitro biochemistry, genetics, proteomics and cell biology. He joined the ICR in October 2018 as a Sir Henry Dale Fellow.
Researchers in this group
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Email: [email protected]
Location: Chelsea
Manuel obtained his PhD from the University of Birmingham in 2018. In January 2019 he joined Dr Gideon Coster's lab at the ICR to investigate mismatch repair and DNA replication.
Dr Gideon Coster's group have written 12 publications
Most recent new publication 2024
See all their publicationsCancer is a disease of uncontrolled proliferation. As cells are pushed into shorter cell cycles, they experience replication stress, which drives genomic instability and disease progression.
While this is generally true for all cancers, it is exemplified by colorectal cancer, which is the third most prevalent cancer in the world and responsible for over 700,000 deaths every year. In 15% of these cases, the underlying cause is inactivation of mismatch repair (MMR), the major pathway for repair of replicative errors. This means that unrepaired errors introduced during normal chromosomal DNA replication are sufficient to drive tumorigenesis.
Replication accuracy is not equal across the human genome. Certain regions, especially repetitive and structure-prone sequences, present a challenge to the replication machinery.
This manifests in MMR-deficient tumours as genetic aberrations of short repetitive sequences termed microsatellites. While microsatellite instability (MSI) was adopted very early on as a diagnostic and prognostic cancer marker, it is now thought to play a causative role. Multiple tumour suppressor genes, such as APC and BAX, harbour frameshift mutations in coding microsatellite regions in MSI-positive tumours.
We know remarkably little about the events that occur as the replication machinery encounters challenging templates. We are working on closing this knowledge gap, with the hope of identifying novel therapeutic approaches and potential drug targets.
This may also lead to improvement of MSI as a diagnostic and prognostic marker. For example, compounds that modulate the accuracy of repeat replication may suppress the occurrence of driver mutations within coding microsatellites in MMR-deficient patients.
Most of our understanding of the interplay between repeats, replication and genomic instability stems from studies of one specific category of microsatellites – trinucleotide repeats (TNRs).
Expansion of TNRs causes a multitude of heritable neurodegenerative disorders such as Fragile X syndrome and myotonic dystrophy. Over two decades of genetic studies have revealed that repeats can impair DNA replication in vivo, and that replication can induce repeat instability.
However, additional DNA metabolism pathways are also implicated in repeat instability, and definitive mechanistic insight is lacking. We are using a highly defined eukaryotic reconstituted replication system, complemented with structural, genetic, proteomic and cell-based approaches.
The results will unravel the mechanisms that dictate the fidelity of repeat replication, will contribute to our understanding of cancer aetiology and may also uncover exciting new approaches and targets for cancer therapy.
Recent discoveries from this group
Scientists uncover key mechanism linking DNA replication to cancer
