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Professor Michael Neuberger FRS

Research Interests

Enzymatic modification of DNA leading to mutation is a molecular event essential to both innate and adaptive immunity. Thus, the elaboration of high affinity IgG antibodies depends upon somatic hypermutation at the IgV gene and class-switch recombination at the IgC.

Both these processes are triggered by targeted deamination of deoxycytidine (dC) to deoxyuridine (dU) residues within the immunoglobulin locus - a process catalysed by the AID enzyme.

A similar process (dC→dU deamination within retroviral first-strand cDNA replication intermediates) underpins a pathway of innate restriction of retroviral (eg HIV) infection: this is mediated by the AID-related APOBEC3 enzymes.

We are interested in (i) the biochemistry of AID/APOBEC enzymes; (ii) the mechanism by which they target their DNA substrate; (iii) the physiological pathways by which programmed dC deamination lead to antibody diversification and the restriction of retroviral infection; (iv) attempts to recapitulate AID-mediated a ntibody maturation in vitro.

Keywords

antibody engineering ; autoimmunity ; genetics ; B cell receptor (BCR) ; B cells ; diversity ; monoclonal antibodies ; isotype switching ; class-switching ; affinity maturation ; antibody responses ; animal models ; carbohydrate biology ; somatic hypermutation ; protein structure/folding ; antibody ; activation

Topics

  • autoimmunity
  • cancer

Key Publications

Häsler, J., Rada, C., and Neuberger. M.S. (2011).
Cytoplasmic activation-induced cytidine deaminase (AID) exists in stoichiometric complex with translation elongation factor 1α (eEF1A).
Proc Natl Acad Sci USA 108, 18366-18371.

Sato,Y., Probst, H.C., Tatsumi, R., Ikeuchi, Y., Neuberger, M.S. and Rada, C. (2010).
Deficiency in APOBEC2 leads to a shift in muscle fiber-type, diminished body mass and myopathy.
J. Biol. Chem.. 285, 7111-7118.

Wang, M., Yang, Z., Rada, C. and Neuberger, M.S. (2009).
AID upmutants isolated using a high-throughput screen highlight the immunity/cancer balance limiting DNA deaminase activity.
Nature Structural & Molecular Biology 16, 769-776.

Conticello S.G., Ganesh K., Xue K., Lu M., Rada C. and Neuberger M.S. (2008)
Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1.
Mol. Cell 31, 474-484.