Dr Takashi Ochi

Profile

I graduated from the department of Physics, Keio University, Japan where I also completed my master degree and studied biophysics and protein crystallography. I then undertook my PhD degree under the supervision of Prof. Sir Tom Blundell's group at the department of Biochemistry, University of Cambridge and studies structures of DNA ligase IV/XRCC4 complex, which works in non-homologous end joining (NHEJ) for DNA double-strand break repair. I stayed in Prof. Blundell's group as a postdoc and, during this time, I determined the crystal structure of the catalytic core of human DNA ligase IV in complex with Artemis nuclease and also discovered a NHEJ factor PAXX for the first time. I then worked with Dr Mark van Breugel as his postdoc at MRC Laboratory of Molecular Biology, Cambridge and studied structures of centrosomes and cilia using cryo-EM, X-ray crystallography, biochemistry, biophysics and cell biology.

Research interests

The centrosome is a major microtubule-organising centre (MTOC) and probably the largest protein assembly having a few hundred-nanometer dimension and found in aminal cells. The centrosome is comparised of a pair of centrioles surrounded by pericentriolar matral (PCM) and centriolar satellites. The centriole has a characteristic 9-fold rotational symmetry, which is created by nine copies of parallely aligned-microtubule blades. One of the centriole pair has appendage structures that are crucial for generating a cilium. Cilia have further extended-microtubule blades (axoneme) from centrioles, which are called basal bodies at cilia. Centrioles and basal bodies are essential the same structure, but their accessary structures are slightly different. Cilia can be largely classified into motile and non-motile. Motile cilia, which can be found more than one per cell, generated fluid flow in our airway, reproduction system & brain and locomotion for sperm cells. Many unicellular organisms such as green algae also use cilia to swim in fresh water. Non-motile cilia (primary cilia) are present one per cell and mediate intra-cellular signal transductions (e.g. hedgehog signalling). Inherited mutantions in genes related to these organells result in human diseases ciliopathies. Ideally, we want to explain exact mechanisms why mutations in centrosomal / ciliary genes cause diseases. However, this is challenging because a large number of genes involve in centrosomal and ciliary functions (e.g. proteomics studies identified >100 proteins associate with centrosomes), and we do not know many of their functions. Thus, studying molecular mechanisms of centrosomal and ciliary functions contribute to understand disease-causing mechanisms as well as to gain knowledge of basic biology.

Our group focuses on determining the atomic stuctures of centrosomes and basal bodies. In order to achieve this, we take both top-down and bottom-up approaches. For the top-down approach, we use cryo-electron tomography (cryo-ET) to observe and characterise the whole centrosomes and basal bodies. For the bottom-up approach, we focus on single protein or sub-complexes of centrosomal / basal body proteins to determine their structures using X-ray crystallography & cryo-EM and their functrions using biochemical/biophysical studies. Proteins that we are currently interested in are the ones belong to the XRCC4/SAS6 superfamily.

This superfamily is comprised of four proteins SAS6, XRCC4, XLF and PAXX, which all share a similar protein fold. SAS6 is a centriolar protein and is the core of a sub-structure of the centriole called the cartwheel, which is key to generate the 9-fold rotational symmetry of the centriole. Remarkably, SAS6 itself assembles into a ring structure having a 9-fold rotational symmetry to scaffold other centrosomal proteins. On the other hand, XRCC4, XLF and PAXX play roles in non-homologous end joining (NHEJ) DNA repair for DNA double-strand breaks. XRCC4 and XLF scaffold two broken DNA ends by forming helical filaments using a similar interface that SAS6 uses to make its ring structure. Therefore, these proteins interestingly use a similar oligomersation mechanism to play a role as scaffold in two different biological systems.

<h4>Research projects</h4> <p>Any research projects I'm currently working on will be listed below. Our list of all <a href="https://biologicalsciences.leeds.ac.uk/dir/research-projects">research projects</a> allows you to view and search the full list of projects in the faculty.</p>

Qualifications

  • PhD, University of Cambridge
  • MSc, Keio University
  • BSc, Keio University

Professional memberships

  • Biochemical Society
<h4>Postgraduate research opportunities</h4> <p>We welcome enquiries from motivated and qualified applicants from all around the world who are interested in PhD study. Our <a href="https://biologicalsciences.leeds.ac.uk/research-opportunities">research opportunities</a> allow you to search for projects and scholarships.</p>