Structural and molecular cell biology
This is a broad theme that involves the study of fundamental cellular processes including the cell cycle, DNA repair, the control of gene expression, protein synthesis, the roles of organelles, trafficking of cell molecules and production of various important metabolites.
Cell cycle research has a strong history in Cambridge. The discovery of the cyclins, which are proteins whose level was found to vary during the cycle, was a key step. Cyclins have turned out to be critical to the control of the cell cycle across a wide range of organisms and are still under very active investigation. This work includes studies of cyclin dependent kinases and their substrates, which are also key parts of the regulatory processes involved. The importance of the regulation of DNA replication to the cell cycle impacts upon the understanding and diagnosis of human cancer. Many aspects of the cell cycle have been highly conserved during evolution so a range of organisms can be used to advantage. The simpler systems of Archaea act as useful models, providing a "stripped down" system of the cell cycle machinery found in eukaryotes. Drosophila and Xenopus are other model organisms in common use.
Recognition and repair of DNA damage are closely linked to cell cycle regulation. A series of checkpoint mechanisms arrest cell cycle progression until damage is repaired. Studies of how DNA repair complexes are assembled have shown that the DNA damage response is triggered by the short telomeres of human cells undergoing replicative senescence. DNA damage responses are influenced by chromatin structure. Several chromatin proteins are known to have roles in both DNA repair and transcription. The regulation of transcription by acetylases, methylases and kinases, which modify histones is also being studied. Studies include the interactions of histones and other proteins with chromatin, which fix its architecture to allow correct gene expression. The integration of these processes with cell cycle progression is being studied in relation to its importance in developing therapeutics for cancer treatment.
The control of gene expression may occur through alternative splicing patterns that produce mRNAs encoding subtly different proteins from the same gene. How a particular splice pattern is prevented from occurring is being studied using in vitro assays to look at the roles of regulatory factors and 3' splice site selection. Other investigations include the roles of 3' untranslated regions and their binding proteins in the repression of translation and the polyA binding protein that participates in regulating the onset of translation upon fertilisation.
Work on organelles includes studying mitochondria, which play a key role in programmed cell death, and chloroplasts of a variety of organisms, including their genomes, targeting and translocation of proteins, electron transfer and ATP synthesis. Studies of the Golgi apparatus in plant cells have shown how sugars are transferred onto membrane proteins or used directly in cell wall synthesis. The biogenesis of post-Golgi compartments is being studied in animal cells in relation to health and disease as is the involvement of trafficking through coated vesicles. Others are studying how growth factors and lipoproteins become internalised into animal cells and the role of the secretory pathway in the assembly of sodium channel subunits. The trafficking of receptors in the CNS is being studied. Studies of how ABC (ATP-binding cassette) transporters recognise and pump their substrates have considerable importance for a number of diseases such as cystic fibrosis and in the development of multi-drug resistance.
The increasing number of sequenced genomes and large scale studies of protein interactions leads to a need to both identify sequence homologues where the level of sequence conservation is low and build models of proteins and complexes whose structure is unknown. The importance of understanding protein folding is highlighted by our increasing awareness of how protein mis-folding leads to diseases such as Alzheimer's disease, Huntington's disease and alpha-1 anti-trypsin deficiency.
There is great strength in the techniques used to study macromolecular structure: X-ray crystallography, NMR spectroscopy, and the various different types of microscopy. There is a focus upon the development of new methodology both experimental and computational, including the international project CCPN. We are moving towards greater integration of the structural biology groups with groups using proteomics, microarrays and other system-wide approaches. There will also be further development of links with colleagues in Mathematics and Physics in the developing area of systems biology. In addition to trying to understand systems of fundamental importance, there is increasing interest in exploiting this knowledge for chemical biology and development of therapeutics.