Michael Neuberger & Cristina Rada

Immunity and DNA deamination

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.

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.

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.

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Group Members

Yasuhiro Uchimura
Anita Chandra
Gareth Williams
Febe Van Maldegem
Ben Taylor
Alfred Lim
Yee Ling Wu
Felix Dingler
Alexander Shapson-Coe
Stephanie Telerman
Julia Reinert

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 antibody maturation in vitro.

MRC Laboratory of Molecular Biology