Macromolecular Structure and Function

p97 X-Ray Model

p97 X-Ray Model

Research Projects

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Research Projects

Our lab uses x-ray crystallography, electron microscopy and nuclear magnetic resonance spectroscopy to obtain structural information about the protein complexes we are studying.  A large variety of biochemical and biophysical techniques are used to complement the structural work.  Ultimately, our scientific interest lies in understanding the mechanism, function and regulation of biologically important protein complexes.

Our current research projects fall broadly into four areas:

  • In addition, some of the members of our lab are involved in the recently established Centre for Synthetic Biology and Innovation at the Institute of Systems and Synthetic Biology, a collaborative effort headed by Professors Paul Freemont and Richard Kitney.  Related to that centre is our involvement with the international Genetically Engineered Machine competition.  We are also part of the Syntegron consortium, an international effort to develop complex synthetic systems.  Lastly, our lab has launched a collaboration with the Drug Discovery Centre at Imperial College.

    Below are short summaries of our projects with links to more profound descriptions.  Please feel free to contact us with any question or suggestion.

    Transcriptional regulation

    Transcription is a fundamental process of life, allowing organisms to utilise the information stored in DNA to respond to the changing environment.  There are three stages of transcription:  activation, elongation and termination.  Research in the lab focuses on understanding how transcription is regulated during the activation and elongation phases.

    Activation is tightly controlled by regulator proteins, which allow genes to be turned on and off in order for cells to develop, differentiate and adapt.  Regulators are often the final players in complex signalling pathways.  Read more.

    Elongation is characterised by the rapid and processive transcription of DNA, which is promoted by transcription elongation factors; these communicate with RNAP and regulate the velocity of RNA synthesis, transcriptional pausing and termination.  Read more.

    The AAA ATPase p97 and associated partners

    p97 is a member of the AAA (ATPase associated with various cellular activities) ATPase family and is an essential protein, conserved throughout evolution from mammals to archaea.  p97 may be thought of as a motor protein that binds to adaptor proteins and transfers energy from ATP binding and hydrolysis through the adaptor to participate in cellular functions such as Golgi reassembly, ubiquitin proteasome degradation and spindle disassembly at the end of mitosis.  The mechanism by which p97 and its adaptors perform these tasks is poorly understood.  Read more.

    Key components in the DNA damage response

    DNA is exposed to toxic chemicals, UV and other radiation and consequently tens of thousands of DNA bases are damaged each day in every human cell.  Cells have developed sophisticated systems using multi-subunit macromolecular complexes to detect, process and repair this damage in a highly controlled and coordinated fashion.  We are currently using a multi-disciplinary approach to provide a molecular understanding of some of the key events including signaling, chromatin remodeling and DNA damage repair itself.  Read more.

    PML bodies and interphase nuclear organization

    Acute promyelocytic leukemia (APL) manifests as a block in the differentiation of promyelocytes, precursors of the granulocyte/neutrophil pathway, which leads to an accumulation of promyelocytes that infiltrate bone marrow.  This block in differentiation results from a reciprocal translocation event, between promyelocytic leukaemia (PML) protein and retinoic acid receptor alpha (RARA) producing the fusion proteins PML-RARA and RARA-PML.  At the molecular level, normal PML is a nuclear protein localising to discrete subnuclear domains as part of a multi-protein complex termed ND10, Kr bodies, PML oncogenic domains (PODs) or PML nuclear bodies.  Read more.

    Synthetic biology in the Freemont lab

    Synthetic biology is an application-driven field attempting to apply fundamental principles of engineering to the redesign of biological systems, to produce valuable and novel biological functions. The driving force behind the field is the desire to develop robust biological systems rapidly and efficiently. Potential applications of synthetic biology are numerous and range from the production of bio-fuel to the synthesis of biomaterials.  Read more.

    Older projects

    Over the years, we have also studied antibiotic tolerance, the structure of NAP endonucleases and the role of SNARE proteins in membrane fusion.