Our laboratory is interested in mutations, not only their roles in
human cancers but also how these processes can be harnessed to destroy
pathogens. While mutation is often thought of in a negative context,
mutations at the DNA level can also be protective and beneficial. In
the past three years, our research has been instrumental in the
discovery of two fundamental mutation-generating mechanisms. In each,
the purposeful use of mutation governs a potent pathogen defense. One
mechanism protects our cells from retroviruses such as HIV-1, and the
other helps strengthen our antibodies such that an effective immune
response occurs when we are infected. The common link between these
important immune defenses systems is that they are underpinned by
related human proteins that use identical strategies --- the chemical
conversion of the DNA base cytosine into uracil.
Haché, G., K. Shindo, J.S. Albin & R.S. Harris (2008) Evolution of HIV-1 isolates that use a novel Vif-independent mechanism to resist restriction by human APOBEC3G. Current Biology, 18, 819-824. (pubmed)
Chen, K.-M., E. Harjes, P.J. Gross, A. Fahmy, Y. Lu, K. Shindo, R.S. Harris# & H. Matsuo# (2008) Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G, Nature, 452, 116-119 (# correspondence).(pubmed)
Schumacher, A.J., G. Haché, D.A. MacDuff, W.L. Brown & R.S. Harris (2008) The DNA deaminase activity of human APOBEC3G is required for Ty1, MusD and HIV-1 restriction. Journal of Virology, 82, 2652-60 (pubmed)
Chen, K.-M., N.A. Martemyanova, Y. Lu, H. Matsuo# & R.S. Harris# (2007) A structural model of the DNA deaminase domain of APOBEC3G corroborated by extensive mutagenesis experiments. FEBS Letters, 581, 4761-66 (# correspondence). (pubmed)
Jónsson, S.R., R.S. LaRue, M.D. Stenglein, S.C. Fahrenkrug, V. Andrésdóttir & R.S. Harris (2007) The restriction of zoonotic PERV transmissions by human APOBEC3G. PLoS One, 2(9), e893 (8 pages). doi:10.1371/journal.pone.0000893 (pubmed)
Stenglein, M.D. & R.S. Harris (2006) APOBEC3B and APOBEC3F inhibit L1 retrotranspostion by a DNA deamination-independent mechanism. Journal of Biological Chemistry, 281, 16837-41. (pubmed)
Jónsson, S.R., G. Haché, M.D. Stenglein, S.C. Fahrenkrug, V. Andrésdóttir & R.S. Harris (2006) Evolutionarily conserved and non-conserved retrovirus restriction activities of artiodactyl APOBEC3F proteins. Nucleic Acids Research, 34, 5683-94. (pubmed)
MacDuff, D.A., M.S. Neuberger & RS Harris (2006) MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells. Molecular Immunology, 43, 1099-108. (pubmed)
Schumacher, A.J., D.V. Nissley & RS Harris (2005) APOBEC3G hypermutates
genomic DNA and inhibits Ty1 retrotransposition in yeast. Proceedings of
the National Academy of Sciences USA, 102, 9854-9859. pubmed
Haché, G, M.T. Liddament & RS Harris (2005) The retroviral hypermutation
specificity of APOBEC3F and APOBEC3G is governed by the C-terminal DNA cytosine
deaminase domain. Journal of Biological Chemistry, 280, 10920-10924. pubmed
Liddament, M. T., Brown, W. L., Schumacher, A. J., and Harris, R. S. (2004).
APOBEC3F properties and hypermutation preferences indicate activity against
HIV-1 in vivo. Curr Biol 14, 1385-1391. pubmed
Beale, R. C., Petersen-Mahrt, S. K., Watt, I. N., Harris, R. S., Rada, C.,
and Neuberger, M. S. (2004). Comparison of the differential context-dependence
of DNA deamination by APOBEC enzymes: correlation with mutation spectra in
vivo. J Mol Biol 337, 585-596. pubmed
Conticello, S. G., Harris, R. S., and Neuberger, M. S. (2003). The Vif protein
of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G.
Curr Biol 13, 2009-2013. pubmed
Harris, R. S., Bishop, K. N., Sheehy, A. M., Craig, H. M., Petersen-Mahrt,
S. K., Watt, I. N., Neuberger, M. S., and Malim, M. H. (2003). DNA deamination
mediates innate immunity to retroviral infection. Cell 113, 803-809. pubmed
Harris, R. S., Petersen-Mahrt, S. K., and Neuberger, M. S. (2002). RNA editing
enzyme APOBEC1 and some of its homologs can act as DNA mutators. Molecular
Cell 10, 1247-1253. pubmed
Petersen-Mahrt, S. K., Harris, R. S., and Neuberger, M. S. (2002). AID mutates
E. coli suggesting a DNA deamination mechanism for antibody diversification.
Nature 418, 99-103. pubmed
Harris, R. S., Sale, J. E., Petersen-Mahrt, S. K., and Neuberger, M. S.
(2002). AID is essential for immunoglobulin V gene conversion in a cultured
B cell line. Current Biology 12, 435-438. pubmed
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