Mechanisms of Mutation in Immunity and Cancer
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. 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.
A complete list of PubMed publications can be found at pubmed.com; keyword "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.
Primary Articles (selected from >100)
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)
Anderson, B.D. & Harris R.S. (2015) Transcriptional regulation of APOBEC3 antiviral immunity through the CBF-β/RUNX axis. Science Advances, 1(8):e1500296.
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).
Swanton C., McGranahan N., Starrett G.J., & Harris R.S. (2015) APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discovery 5 (704-12).
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-κB signaling pathway induces APOBEC3B expression in multiple human cancers. Cancer Research 5 (21)
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).
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)
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 10 (11)
Refsland E.W. & R.S. Harris. (2013) The APOBEC3 family of retroelement restriction factors. Current topics in microbiology and immunology 371 (1-27).
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. Nature 494 (366-70).
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).