The Denton Prize

The Denton Prize is named for Professor Dick Denton, FRS.

Dick moved to the School of Biochemistry at its inception with his postgraduate supervisor Professor Sir Philip Randle, FRS. He completed his studies in the School in 1966, beginning a long research career at Bristol into insulin signalling and diabetes.

Dick was Head of School from 1995 to 2000 before becoming Dean of the new Faculty of Medical and Veterinary Medicine. Postgraduate students from his laboratory can be found heading research groups of their own in universities and research institutes across the world, including several members of the current School of Biochemistry . In the spirit of this long-standing commitment to research training, the Denton Prize is awarded each year to excellent postgraduate students in the School, and is centered around on a series of postgraduate School seminars.

Professor Denton wishes to make it clear that, despite being associated with an eponymous prize, he is still very much alive.

Ian McGough

2012: A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion

Wnt proteins are lipid-modified glycoproteins that play a central role in development, adult tissue homeostasis and disease. Secretion of Wnt proteins is mediated by the Wnt-binding protein Wntless (Wls), which transports Wnt from the Golgi network to the cell surface for release. It has recently been shown that recycling of Wls through a retromer-dependent endosome-to-Golgi trafficking pathway is required for efficient Wnt secretion, but the mechanism of this retrograde transport pathway is poorly understood.

In collaboration with the laboratory of Dr Rik Korswagen (Hubrecht Institute, The Netherlands) we have shown that Wls recycling is mediated through a retromer pathway that is independent of the retromer sorting nexins SNX1-SNX2 and SNX5-SNX6. We have found that the unrelated sorting nexin, SNX3, has an evolutionarily conserved function in Wls recycling and Wnt secretion and show that SNX3 interacts directly with the cargo-selective subcomplex of the retromer to sort Wls into a morphologically distinct retrieval pathway. These results demonstrate that SNX3 is part of an alternative retromer pathway that functionally separates the retrograde transport of Wls from other retromer cargo and is a crucial mediator of Wnt morphogenic gradient formation.

Sarah Whitehouse

2011: Bacterial protein translocation is mediated by the SecYEG channel and the SecA ATPase

The mechanism by which protein translocation is coupled to ATP hydrolysis and subsequent conformational changes is not fully understood. A recent structure of SecA bound to SecYEG indicated that a two-helix finger domain within SecA is suitably positioned to interact with polypeptide substrates and push them through SecYEG. To test this hypothesis we have cross-linked the tip of the two-helix finger to residues at the periphery of the SecYEG channel, or deep within it. We find that immobilisation at the channel edge permits substrate translocation, but fixation deeper within it blocks transport because the two-helix finger is arrested such that it obstructs the pathway of the translocating polypeptide. Through this approach we show that the SecA two-helix finger remains static during substrate translocation.

Jade Cheng

2010: Roles of the Golgi stacking protein GRASP65 in apoptosis and mitosis

GRASP65 is an important structural and regulatory component of the Golgi apparatus. It links adjacent Golgi stacks and facilitates membrane traffic through the Golgi. During mitosis GRASP65 is phosphorylated, leading to Golgi disassembly, and similarly, GRASP65 cleavage by apoptotic caspases causes Golgi fragmentation. Jade has been studying how caspase cleavage of GRASP65 is needed for efficient apoptosis in response to the Fas death ligand. Jade's data show that GRASP65 does not influence the trafficking of the Fas receptor to the cell surface, but instead, its cleavage during apoptosis releases a toxic fragment that translocates to the mitochondria.

Jade has also been exploring a novel link between GRASP65 and the machinery that controls cytokinesis. GRASP65 binds to the motor Kif14, and Jade is now examining how this interaction coordinates membrane delivery to the midbody.

Chris Pernstich

2009: Characterisation of the FokI restriction endonuclease

The several thousand restriction enzymes identified to date each recognise a specific sequence of bases in DNA, typically between 4 and 8 bp long, and cut both strands of the DNA, usually within their recognition sequence. However, in a substantial number of cases, the restriction enzyme binds to a specific sequence but then reaches out from its binding site to cut both strands of the DNA, not within the recognition site but rather at fixed positions distant from the site, in some cases as far as 20 bp away. Christian has used a combination of protein modification methods and advanced fluorescence techniques to reveal how one such enzyme, the FokI restriction endonuclease, reaches out from its specific binding site to contact its distant sites for DNA cleavage, and how the enzyme organises itself to cut both strands of the DNA at these distant locations.

Joseph Yeeles

2008: AddAB: A machine for processing double-strand DNA breaks

Double-strand DNA breaks occur in all cell types during normal replication in the presence or absence of DNA damaging agents. Since this damage can have catastrophic consequences for a cell, the homologous recombination machinery acts at DNA breaks to promote error-free repair. Joe has been investigating how recombinational repair in Gram-positive bacteria is initiated by the AddAB helicase/nuclease class of enzymes. Biochemical analysis of Bacillus subtilis AddAB has revealed a novel mechanism for the processing of dsDNA breaks. This work has important implications for understanding the architecture of molecular machines that preserve genome integrity.

Ana Cvejic

2007: Live imaging and genetic dissection of WASp function during the wound inflammatory response of Zebrafish larvae

The body responds to wounding by migration of cells of the immune system into to the site of damage. Ana's research uses Zebrafish larvae as a genetic model organism to study the migration of macrophages and neutrophils into wounds. Ana has been particularly interested in a signalling protein called WASp, which in humans is mutated in the genetic disease Wiskott-Aldrich syndrome. Ana showed that loss of the Zebrafish wasp1 gene is important for the migration of immune cells into wound sites, affecting both the speed and directionality of the migration of these cells.

Patients with Wiskott-Aldrich syndrome suffer a range of immune disfunctions, and Ana's work will contribute to the development of new therapies for this and other immune disorders

Mike Tyka and Jon Rea

2006: Ab initio prediction of protein folding

How a protein folds from a newly synthesised peptide chain into a complex 3D structure is one of the big questions in biological sciences. Somehow the information necessary for this process must be present in the peptide sequence, and researchers around the world are working to be able to predict protein structure from primary protein sequence. Jon Rea and Mike Tyka presented their research on the development of computer programs that will allow the prediction of protein structures in silico. Jon's work involved modelling the folding of the loops that join segments of protein structure; whereas Mike modelled the folding of the basic segments themselves. Both showed how development of the the modelling algorithms had allowed them to make improvements in the accuracy of the structure prediction. The joint award recognises the quality of both sets of work, and also how Jon and Mike have worked co-operatively over their PhDs to solve these problems.

Jonathan Astin

2005: Vampire worms - UV sensitivity in C. elegans

In humans, repair of UV-induced DNA damage is dependent on the multi-step nucleotide excision repair (NER) system. An absence of NER activity in humans results in the disorder xeroderma pigmentosum. Patient with this disease suffer from extreme photosensitivity and a high incidence of skin cancers. Jonathan presented his research into DNA repair mechanisms in the nematode worm C. elegans. He showed that a mutant C. elegans strain that is highly sensitive to UV contains a mutation to the rad-3 gene, whose human counterpart is the gene responsible for human xeroderma pigmentosum.

Jonathan's work with this gene using nematode worms highlighted novel information about how defects in this gene affect DNA repair, contributing to our understanding of this process in humans.