Research Program: Genetic Mechanisms of Cancer
Assistant Professor, Department of Biochemistry, Molecular Biology and Biophysics

rsh@umn.edu
612-624-0457 — office
612-624-0459 — lab
Preferred method of contact: e-mail

Research Interests

Understanding mechanisms of directed mutation in humans

The main long-term goal of my laboratory is to understand the physiological roles and pathological consequences of programmed mutation in humans. Mutations drive evolution and are mostly responsible for the tremendous variation observed between different organisms and even within an individual species. Most mutations are thought to occur 'spontaneously', without a direct or immediate need for their utility. However, this is not always the case as at least two important physiological processes — antibody gene diversification and retroelement restriction — are triggered by the deamination of DNA cytosines to uracils. The human proteins responsible are called AID and APOBEC3F/G, respectively. These proteins are potent DNA mutators that must be directed to their specific physiological targets, to immunoglobulin genes or to retroviruses (e.g., HIV-1) and retrotransposons. We are using a number of model systems to understand how AID and APOBEC3 proteins are regulated at the post-translational level. We anticipate that both unique and common themes will emerge. Moreover, we expect that by understanding how these proteins are regulated normally, we will gain insight into the possible consequences when they are not (e.g., cancer).

Selected Publications

Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH. DNA deamination mediates innate immunity to retroviral infection. Cell 2003;113:803-809.

Liddament MT, Brown WL, Schumacher AJ, Harris RS. APOBEC3F properties and hypermutation preferences indicate activity against HIV-1 in vivo. Curr Biol. 2004;14:1385-1391.

Harris RS, Liddament MT. Retroviral restriction by APOBEC proteins. Nat Rev Immunol. 2004;4:868-877.

Haché G, Liddament MT, Harris RS. The retroviral hypermutation specificity of APOBEC3F and APOBEC3G is governed by the C-terminal DNA cytosine deaminase domain. J Biol Chem. 2005;280,10920-10924.

Schumacher AJ, Nissley DV, Harris RS. APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast. Proc Natl Acad Sci USA. 2005;102:9854-9859.

MacDuff DA, Neuberger MS, Harris RS. MDM2 can interact with the C-terminus of AID but it is inessential for antibody diversification in DT40 B cells. Mol Immunol. 2006;43:1099-1108.

Stenglein MD, Harris RS. APOBEC3B and APOBEC3F inhibit L1 retrotranspostion by a DNA deamination-independent mechanism. J Biol Chem. 2006;281:16837-41.

Harris RS, Matsuo H. Dancin' deaminase! Nat Struct Mol Biol. 2006;13:380-81.

Jónsson SR, Haché G, Stenglein MD, Fahrenkrug SC, Andrésdóttir V, Harris RS. Evolutionarily conserved and non-conserved retrovirus restriction activities of artiodactyl APOBEC3F proteins. Nucleic Acids Res. 2006;34:5683-94.

Haché G, Mansky LM, Harris RS. Human APOBEC3 proteins, retrovirus restriction and HIV drug resistance. AIDS Rev. 2006;8:148-57.

Jónsson SR, LaRue RS, Stenglein MD, Fahrenkrugc SC, Andrésdóttir V, Harris RS. The restriction of zoonotic PERV transmissions by human APOBEC3G. PLoS One 2007;2:e893.

Chen K-M^*, Martemyanova NA^*,Lu Y, Matsuo H^#, Harris RS^#. A structural model of the DNA deaminase domain of APOBEC3G corroborated by extensive mutagenesis experiments. FEBS Lett 2007;581:4761-66. (^*equal contributions; ^#correspondence).

Schumacher AJ, Haché G, MacDuff DA, Brown WL, Harris RS. The DNA deaminase activity of human APOBEC3G is required for Ty1, MusD and HIV-1 restriction. J Virol. 2007;82: 2652-60.

Chen K-M^*, Harjes E^*, Gross PJ^*, Fahmy A, Lu Y, Shindo K, Harris RS^#, Matsuo H^#. Structure of the DNA deaminase domain of the HIV-1 restriction factor APOBEC3G. Nature 2008; 452:116-119. (^*equal contributions; ^#correspondence).

Haché G, Shindo K, Albin JS, Harris RS. Evolution of HIV-1 isolates that use a novel Vif-independent mechanism to resist restriction by human APOBEC3G. Curr Biol. 2008;18:819-824.