Reuben Harris, PhD
The Harris Lab uses a large repertoire of model systems and experimental approaches to understand how DNA mutating enzymes (APOBECs) provide immunity against viral infections, yet in many cases also contribute to tumor evolution through genomic DNA mutagenesis. Another goal of the Harris Lab is to translate these fundamental scientific discoveries into novel therapeutics against viruses and cancer.
Mechanisms of purposeful mutation, Innate and adaptive immunity
Awards & Recognition
Professor and HHMI Investigator, and Biophysics Department of Biochemistry, Molecular Biology
Associate Director, Institute for Molecular Virology
Faculty, MS and PhD Programs in Pharmacology
Faculty, Masters Program in Stem Cell Biology
PhD, University of Alberta, 1997
Mechanisms of Mutation in Immunity and Cancer Biology
Human cells have the capacity to produce up to nine active DNA cytosine deaminases. The seven-member APOBEC3 subfamily provides an innate immune barrier to a wide variety of DNA based parasites including transposons and viruses such as HIV-1. One family member, AID, also has an essential role in adaptive immunity by promoting antibody diversification through isotype switch recombination and somatic hypermutation. The founding family member, APOBEC1, has a role in mRNA editing, but is also likely to have innate immune functions. Despite these beneficial activities, a subset of these enzymes also poses a threat to nuclear DNA. Recent studies have revealed a major role for DNA cytosine deamination in mutagenesis in breast, head/neck, cervical, bladder, lung, and other cancer types. The Harris Lab uses a large repertoire of model systems and experimental approaches to understand how DNA mutating enzymes (APOBECs) provide immunity against viral infections, yet in many cases also contribute to tumor evolution through genomic DNA mutagenesis. Another goal of the Harris Lab is to translate these fundamental scientific discoveries into novel therapeutics against viruses and cancer.
Complete list of PubMed publications available at pubmed.com; key word “Reuben Harris”
Tennyson RL, Walker SN, Ikeda T, Harris R.S., Kennan AJ, McNaughton BR. Chembiochem. (2016) Helix-Grafted Pleckstrin Homology Domains Suppress HIV-1 Infection of CD4-Positive Cells. 17(20):1945-1950. doi: 10.1002/cbic.201600329.
Law EK, Sieuwerts AM, LaPara K, Leonard B, Starrett GJ, Molan AM, Temiz NA, Vogel RI, Meijer-van Gelder ME, Sweep FC, Span PN, Foekens JA, Martens JW, Yee D, Harris R.S. (2016) The DNA cytosine deaminase APOBEC3B promotes tamoxifen resistance in ER-positive breast cancer. Sci Adv. 7;2(10):e1601737.
Starrett G.J., Luengas E.M., McCann J.L., Ebrahimi D., Temiz N.A., Love R.P., Feng Y., Adolph M.B., Chelico L., Law E.K., Carpenter M.A., & Harris R.S. (2016) The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis. Nature Communications. 7:12918. doi: 10.1038/ncomms12918.
Akre M.K., Starrett G.J., Quist J.S., Temiz N.A., Carpenter M.A., Tutt A.N., Grigoriadis A., & Harris R.S. (2016) Mutation Processes in 293-Based Clones Overexpressing the DNA Cytosine Deaminase APOBEC3B. PLoS One, 11(5):e0155391.
Verhalen B., Starrett G.J., Harris R.S., & Jiang M. (2016) Functional Upregulation of the DNA Cytosine Deaminase APOBEC3B by Polyomaviruses. Journal of Virology, 90(14):6379-86.
Shaban N.M., Shi K., Li M., Aihara H., & Harris R.S. (2016) 1.92 Angstrom Zinc-Free APOBEC3F Catalytic Domain Crystal Structure. Journal of Molecular Biology, 428(11):2307-16.
Leonard B., Starrett G.J., Maurer M.J., Oberg A.L., Van Bockstal M., Van Dorpe J., De Wever O., Helleman J., Sieuwerts A.M., Berns E.M., Martens J.W., Anderson B.D., Brown W.L., Kalli K.R., Kaufmann S.H.,& Harris R.S. (2016) APOBEC3G Expression Correlates with T-Cell Infiltration and Improved Clinical Outcomes in High-grade Serous Ovarian Carcinoma. Clinical Cancer Research, Epub March 25.
Richards C., Albin J.S.m Demir Ö., Shaban N.M., Luengas E.M., Land A.M., Anderson B.D., Holten J.R., Anderson J.S., Harki D.A., Amaro R.E., & Harris R.S. (2015) The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches. Cell Reports, 13(9):1781-8.
Anderson, B.D. & Harris R.S. (2015) Transcriptional regulation of APOBEC3 antiviral immunity through the CBF-?/RUNX axis. Science Advances, 1(8):e1500296.
Land A.M., Wang J., Law E.K., Aberle R., Kirmaier A., Krupp A., Johnson W.E., & Harris R.S. (2015) Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif. Oncotarget, 6(37):39969-79.
Leonard B., McCann J.L., Starrett G.J., Kosyakovsky L., Luengas E.M., Molan A.M., Burns M.B., McDougle R.M., Parker P.J., Brown W.L., & Harris R.S. (2015) The PKC/NF-?B signaling pathway induces APOBEC3B expression in multiple human cancers. Cancer Research, 5(21):4538-47.
Shi K., Carpenter M.A., Kurahashi K., Harris R.S., & Aihara H. (2015) Crystal Structure of the DNA deaminase APOBEC3B catalytic domain. Journal of Biological Chemistry, 290(47):28120-30.
Olson M.E., Abate-Pella D., Perkins A.L., Li M., Carpenter M.A., Rathore A., Harris R.S., & Harki D.A. (2015) Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries. Journal of Medicinal Chemistry, 58(18), 7419-30.
Swanton C., McGranahan N., Starrett G.J., & Harris R.S. (2015) APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity. Cancer Discovery, 5(7), 704-12.
Kouno T., Luengas E.M., Shigematsu M., Shandilya S.M., Zhang J., Chen L., Hara M., Schiffer C.A., Harris R.S., & Matsuo H. (2015) Structure of the Vif-binding domain of the antiviral enzyme APOBEC3G. Nature Structural and Molecular Biology, 22(6), 485-91.
Kane J.R., Stanley D.J., Hultquist J.F., Johnson J.R., Mietrach N., Binning J.M., Jónsson S.R., Barelier S., Newton B.W., Johnson T.L., Franks-Skiba K.E., Li M., Brown W.L., Gunnarsson H.I., Adalbjornsdóttir A., Fraser J.S., Harris R.S., Andrésdóttir V., Gross J.D., & Krogan N.J. (2015) Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity. Cell Reports, 11(8), 1236-50.
Harris, R.S. (2015) Molecular mechanism and clinical impact of APOBEC3B-catalyzed mutagenesis in breast cancer. Breast Cancer Research, 17, 8.
Harris, R.S., & Dudley, J.P. (2015) APOBECs and virus restriction. Virology, 479-480, 131-45.
Land A.M., Shaban N.M., Evans L., Hultquist J.F., Albin J.S., & Harris R.S. (2014) APOBEC3F determinants of HIV-1 Vif Sensitivity. Journal of Virology.
Albin J.S., Brown W.L., & Harris R.S. (2014) Catalytic activity of APOBEC3F in required for efficient restriction of Vif-deficient human immunodeficiency virus. Virology.
Vieira V.C., Leonard B., White E.A., Starrett G.J., Temiz N.A., Lorenz L.D., Lee D., Soares M.A., Lambert P.F., Howley P.M., & Harris R.S. (2014) Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B. mBio, 5(6).
Refsland E.W., Hultquist J.F., Luengas E.M., Ikeda T., Shaban N.M., Law E.K., Brown W.L., Reilly C., Emerman M., & Harris R.S. (2014) Natural polymorphisms in human APOBEC3H and HIV-1 Vif combine in primary T lymphocytes to affect viral G-to-A mutation levels and infectivity. PLOS Genetics.
Leonard B., Hart S.N., Burns M.B., Carpenter M.A., Temiz N.A., Rathore A., Vogel R.I., Nikas J.B., Law E.K., Brown W.L., Li Y., Zhang Y., Maurer M.J., Oberg(2013) APOBEC3B upregulations and genomic mutation patterns in serious ovarian carcinoma. Cancer Res, 73(24), 7222-31.
Rathore, A., M.A. Carpenter, Ö. Demir, T. Ikeda, M. Li, N.M. Shaban, E.K. Law, D. Anokhin, W.L. Brown, R.E. Amaro, & R.S. Harris. (2013) The Local Dinucleotide Preference of APOBEC3G Can Be Altered from 5'-CC to 5'-TC by a Single Amino Acid Substitution. Journal of Molecuar Biology, Epub: Aug 11.
Burns M.B., N.A. Temiz, & R.S. Harris. (2013) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics, 45, 977-83.
Refsland E.W. & R.S. Harris. (2013) The APOBEC3 family of retroelement restriction factors. Current Topics in Microbiology and Immunology, 371, 1-27.
Bohn M., S.M. Shandilya, J.S. Albin, T. Kouno, B.D. Anderson, R.M. McDougle, M.A. Carpenter, A. Rathore, L. Evans, A.N. Davis, J. Zhang, Y. Lu, M. Somasundaran, H. Matsuo, R.S. Harris, & C.A. Schiffer. (2013) Crystal structure of the DNA cytosine deaminase APOBEC3F: the catalytically active and HIV-1 Vif-binding domain. Structure, 21, 1042-50.
Land A.M., E.K. Law, M.A. Carpenter, L. Lackey, W.L. Brown, & R.S. Harris. (2013) Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and nongenotoxic. Journal of Biological Chemistry, 288, 17253-60.
Burns M.B., L. Lackey, M.A. Carpenter, A. Rathore, A.M. Land, B. Leonard, E.W. Refsland, D. Kotandeniya, N. Tretyakova, J.B. Nikas, D. Yee, N.A. Temiz, D.E. Donohue, R.M. McDougle, W.L. Brown, E.K. Law, & R.S. Harris. (2013) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature, 494, 366-70.
Original Discoveries (Classics):
APOBEC3B is a major source of cancer mutagenesis:
Burns*, M.B., L. Lackey*, M.A. Carpenter, A. Rathore, A.M. Land, B. Leonard, E.W. Refsland, D. Kotandeniya, N. Tretyakova, J.B. Nikas, D. Yee, N.A. Temiz, D.E. Donohue, R.M. McDougle, W.L. Brown, E.K. Law & R.S. Harris (2013) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature494:366–370 (*equal contributions).
Burns M.B., N.A. Temiz, & R.S. Harris. (2013) Evidence for APOBEC3B mutagenesis in multiple human cancers. Nature Genetics 45 (977-83).
Cellular CBF-beta is a Vif co-factor required for HIV-1 pathogenesis:
Jäger*, S., D.Y. Kim*, J.F. Hultquist*, K. Shindo, R.S. LaRue, E. Kwon, M. Li, B.D. Anderson, L. Yen, D. Stanley, C. Mahon, J. Kane, K. Franks-Skiba, P. Cimermancic, A. Burlingame, A. Sali, C. Craik, R.S. Harris#, J.D. Gross# & N.J. Krogan# (2011) Vif hijacks CBF-b to degrade APOBEC3G and promote HIV-1 infection. Nature 481 (371-5) (*equal contributions; #correspondence).
APOBEC3G antiviral activity and the DNA deamination mechanism for retrovirus restriction:
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 (803-9).
APOBEC family members are DNA cytosine deaminases:
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 (1247-53).
AID is a DNA deaminase that catalyzes antibody gene diversification:
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) (* equal contributions).