Wolfson Institute for Biomedical Research

The Wolfson Institute for Biomedical Research
at the Cruciform Building

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Prof. Gareth H. Williams and Dr. Kai Stoeber
- 020 76796304 / gareth.williams@ucl.ac.uk
- 020 76796302 / k.stoeber@ucl.ac.uk

Chromosomal Replication Group

Lab summary

The Chromosomal Replication Group focuses on the DNA replication licensing pathway, its molecular elucidation and translation of knowledge gained through basic scientific research to clinical practice.

This pathway lies at the convergence point of major oncogenic growth signalling pathways, making it an attractive target for diagnostic and therapeutic intervention. We have shown, for example, that the Mcm2-7 licensing factors, core constituents of the DNA replicative helicase, can be used to detect pre-cancerous growth (dysplasia) in a range of organ systems and have major potential to improve the sensitivity of the cervical Pap smear test used in population screening.

Through a combination of biochemistry, biophysics and structural biology, we are now analysing selected protein-protein and protein-DNA interactions critical for replication initiation, including those involved in the assembly of pre-replication complexes (geminin/Cdt1) and origin firing (Cdc7/ASK). This approach has enabled us to characterise origin licensing and activation at the molecular level and has provided novel mechanistic strategies for anticancer therapeutic intervention.

We have recently shown that inhibition of the DNA replication initiation machinery, using a peptide transporter coupled to geminin, or, alternatively, Cdc7 kinase inhibitors, can achieve potent cancer-cell-selective killing due to impairment/loss of a checkpoint for replication-competent origins in transformed cells. A major focus of our research is now directed towards elucidating the molecular nature of this novel cell cycle checkpoint. Using a combination of gene expression arrays and proteomics, we have already identified several central players in the underlying molecular circuitry.

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Selected publications

Loddo M, Kingsbury SR, Rashid M, et al. (2009) Cell-cycle-phase progression analysis identifies unique phenotypes of major prognostic and predictive significance in breast cancer. Br.J. Cancer. 100:959-970.

Roberts S, Kingsbury SR, Stoeber K, et al. (2008) Identification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA synthesis in vitro and in cells. J. Virol. 82:9056-9064.

Williams GH, Stoeber K. (2007) Cell cycle markers in clinical oncology. Curr. Opin. Cell Biol. 19:672-679.

Okorokov AL, Waugh A, Hodgkinson J, et al. (2007) Hexameric ring structure of human MCM10 DNA replication factor. EMBO Rep. 8:925-930.

Okuyama M, Laman H, Kingsbury SR, et al. (2007) Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells. Nature Methods. 4:153-159.

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Academic Career

TBA

Funding

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