MICaB Graduate Program
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Reuben S. Harris, Ph.D.
Department of Biochemistry, Molecular Biology and Biophysics
University of Alberta, Edmonton, 1997, Ph.D.
Adaptive and innate mechanisms of purposeful mutation
Mutations are generally regarded as harmful, as they can lead to cancer. However, mutations can also be beneficial, as evidenced by the fact that our cellular mutation-making machinery can be harnessed and used to defend us from infection by disease-causing viruses such as HIV (which causes AIDS) and microbes. The Harris laboratory is using a number of model systems to dissect the mechanisms of two purposeful mutation programs --- antibody gene diversification and retroelement restriction. Both programs are catalyzed by potent DNA cytosine deaminases. This research will lead to a better understanding of how beneficial mutations occur, to therapeutic approaches that exploit specific aspects of these mechanisms and to knowledge of how inaccuracies in these processes contribute to cancer.
Selected Recent Publications:
- Albin, J.S., R.S. LaRue, J.A. Weaver, E. Harjes, H. Matsuo & R.S. Harris (2010) A single amino acid in human APOBEC3F alters susceptibility to HIV-1 Vif. Journal of Biological Chemistry, 285, 40785-92.
- LaRue, R.S., J. Lengyel, S.R. Jónsson, V. Andrésdóttir & R.S. Harris (2010) Lentiviral Vif degrades the APOBEC3Z3/APOBEC3H protein of its mammalian host and is capable of cross-species activity. Journal of Virology, 84, 8193-8201.
- Refsland, E.W., M.D. Stenglein, K. Shindo, J.S. Albin, W.L. Brown & R.S. Harris (2010) Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic Acids Research, 38, 4274-84.
- Stenglein, M.D., M.B. Burns, M. Li, J. Lengyel & R.S. Harris (2010) APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nature Structure and Molecular Biology, Feb;17(2):222-9.
- Hultquist, J.F. & R.S. Harris (2009) Leveraging APOBEC3 proteins to alter the HIV mutation rate and combat AIDS. Future Virology, 4, 605-619.
- MacDuff, D.A., Z.L. Demorest & R.S. Harris (2009) AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity. Nucleic Acids Research, 37, 1854-1867.
- 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.
- 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.
- 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.
- MacDuff, D.A., M.S. Neuberger & R.S. 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, 1099-1108
- Haché, G, M.T. Liddament & R.S. 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.
- Schumacher, A.J., D.V. Nissley & R.S. Harris (2005) APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast. Proceedings of the National Academy of Sciences USA, 102, 9854-9859.
- Liddament, M.T., W.L. Brown, A.J. Schumacher & R.S. Harris (2004) APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo. Current Biology, 14, 1385-1391.
- Harris, R.S. & M.T. Liddament (2004) Retroviral restriction by APOBEC proteins. Nature Reviews Immunology, 4, 868-877.
- Harris, R.S., K.N. Bishop, A.M. Sheehy, H.M. Craig, S.K. Petersen-Mahrt, I.N. Watt, M.S. Neuberger & M.H. Malim (2003) DNA deamination mediates innate immunity to retroviral infection. Cell, 113, 803-809.
- Petersen-Mahrt, S.K., R.S. Harris & M.S. Neuberger (2002) AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature, 418, 99-103.
- Harris, R.S., S.K. Petersen-Mahrt & M.S. Neuberger (2002) RNA editing protein APOBEC1 and some of its homologues can act as DNA mutators. Molecular Cell, 10, 1247-1253.