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11. APOBECs and Herpesviruses

Author

Cheng, Adam Z., primary, Moraes, Sofia N., additional, Shaban, Nadine M., additional, Fanunza, Elisa, additional, Bierle, Craig J., additional, Southern, Peter J., additional, Bresnahan, Wade A., additional, Rice, Stephen A., additional, and Harris, Reuben S., additional

Published
2021
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13. The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase

Author

Serebrenik, Artur A, Starrett, Gabriel J, Leenen, Sterre, Jarvis, Matthew C, Shaban, Nadine M, Salamango, Daniel J, Nilsen, Hilde, Brown, William L, Harris, Reuben S, Serebrenik, Artur A, Starrett, Gabriel J, Leenen, Sterre, Jarvis, Matthew C, Shaban, Nadine M, Salamango, Daniel J, Nilsen, Hilde, Brown, William L, and Harris, Reuben S

Abstract

Human cells express up to 9 active DNA cytosine deaminases with functions in adaptive and innate immunity. Many cancers manifest an APOBEC mutation signature and APOBEC3B (A3B) is likely the main enzyme responsible. Although significant numbers of APOBEC signature mutations accumulate in tumor genomes, the majority of APOBEC-catalyzed uracil lesions are probably counteracted in an error-free manner by the uracil base excision repair pathway. Here, we show that A3B-expressing cells can be selectively killed by inhibiting uracil DNA glycosylase 2 (UNG) and that this synthetic lethal phenotype requires functional mismatch repair (MMR) proteins and p53. UNG knockout human 293 and MCF10A cells elicit an A3B-dependent death. This synthetic lethal phenotype is dependent on A3B catalytic activity and reversible by UNG complementation. A3B expression in UNG-null cells causes a buildup of genomic uracil, and the ensuing lethality requires processing of uracil lesions (likely U/G mispairs) by MSH2 and MLH1 (likely noncanonical MMR). Cancer cells expressing high levels of endogenous A3B and functional p53 can also be killed by expressing an UNG inhibitor. Taken together, UNG-initiated base excision repair is a major mechanism counteracting genomic mutagenesis by A3B, and blocking UNG is a potential strategy for inducing the selective death of tumors.

Published
2019

15. Epstein–Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity

Author

Cheng, Adam Z., primary, Yockteng-Melgar, Jaime, additional, Jarvis, Matthew C., additional, Malik-Soni, Natasha, additional, Borozan, Ivan, additional, Carpenter, Michael A., additional, McCann, Jennifer L., additional, Ebrahimi, Diako, additional, Shaban, Nadine M., additional, Marcon, Edyta, additional, Greenblatt, Jack, additional, Brown, William L., additional, Frappier, Lori, additional, and Harris, Reuben S., additional

Published
2018
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17. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by a RNA-Mediated Dimerization Mechanism

Author

Shaban, Nadine M., primary, Shi, Ke, additional, Lauer, Kate V., additional, Carpenter, Michael A., additional, Richards, Christopher M., additional, Lopresti, Michael W., additional, Salamango, Daniel, additional, Wang, Jiayi, additional, Banerjee, Surajit, additional, Brown, William L., additional, Aihara, Hideki, additional, and Harris, Reuben S., additional

Published
2018
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18. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by a RNA-Mediated Dimerization Mechanism

Author

Shaban, Nadine M., primary, Shi, Ke, additional, Lauer, Kate V., additional, Carpenter, Michael A., additional, Richards, Christopher M., additional, Lopresti, Michael W., additional, Salamango, Daniel, additional, Wang, Jiayi, additional, Banerjee, Surajit, additional, Brown, William L., additional, Aihara, Hideki, additional, and Harris, Reuben S., additional

Published
2017
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19. Abstract 5236: The dynamic interplay between the cancer genome mutating enzyme APOBEC3B and DNA substrates

Author

Demir, Ozlem, primary, Wagner, Jeffrey R., additional, Shi, Ke, additional, Carpenter, Michael A., additional, Banerjee, Surajit, additional, Shaban, Nadine M., additional, Kurahashi, Kayo, additional, Salamango, Daniel J., additional, McCann, Jennifer L., additional, Starrett, Gabriel J., additional, Duffy, Justin V., additional, Harki, Daniel, additional, Aihara, Hideki, additional, Amaro, Rommie E., additional, and Harris, Reuben S., additional

Published
2017
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20. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B

Author

Shi, Ke, primary, Carpenter, Michael A, additional, Banerjee, Surajit, additional, Shaban, Nadine M, additional, Kurahashi, Kayo, additional, Salamango, Daniel J, additional, McCann, Jennifer L, additional, Starrett, Gabriel J, additional, Duffy, Justin V, additional, Demir, Özlem, additional, Amaro, Rommie E, additional, Harki, Daniel A, additional, Harris, Reuben S, additional, and Aihara, Hideki, additional

Published
2016
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23. The Binding Interface between Human APOBEC3F and HIV-1 Vif Elucidated by Genetic and Computational Approaches

Author

Richards, Christopher, primary, Albin, John S., additional, Demir, Özlem, additional, Shaban, Nadine M., additional, Luengas, Elizabeth M., additional, Land, Allison M., additional, Anderson, Brett D., additional, Holten, John R., additional, Anderson, John S., additional, Harki, Daniel A., additional, Amaro, Rommie E., additional, and Harris, Reuben S., additional

Published
2015
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24. Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G.

Author

Jiayi Wang, Shaban, Nadine M., Land, Allison M., Brown, William L., and Harrisa, Reuben S.

Subjects
*SIMIAN immunodeficiency virus, *CYTOSINE deaminase, *ANTISENSE DNA, *REVERSE transcriptase, *CHIMERIC proteins, *VIRAL genetics
Abstract

Several members of the APOBEC3 DNA cytosine deaminase family can potently inhibit Vif-deficient human immunodeficiency virus type 1 (HIV-1) by catalyzing cytosine deamination in viral cDNA and impeding reverse transcription. HIV-1 counteracts restriction with the virally encoded Vif protein, which targets relevant APOBEC3 proteins for proteasomal degradation. HIV-1 Vif is optimized for degrading the restrictive human APOBEC3 repertoire, and, in general, lentiviral Vif proteins specifically target the restricting APOBEC3 enzymes of each host species. However, simian immunodeficiency virus SIVmac239 Vif elicits a curiously wide range of APOBEC3 degradation capabilities that include degradation of several human APOBEC3s and even human APOBEC3B, a non-HIV-1-restricting APOBEC3 enzyme. To better understand the molecular determinants of the interaction between SIVmac239 Vif and human APOBEC3B, we analyzed an extensive series of mutants. We found that SIVmac239 Vif interacts with the N-terminal domain of human APOBEC3B and, interestingly, that this occurs within a structural region homologous to the HIV-1 Vif interaction surface of human APOBEC3G. An alanine scan of SIVmac239 Vif revealed several residues required for human APOBEC3B degradation activity. These residues overlap HIV-1 Vif surface residues that interact with human APOBEC3G and are distinct from those that engage APOBEC3F or APOBEC3H. Overall, these studies indicate that the molecular determinants of the functional interaction between human APOBEC3B and SIVmac239 Vif resemble those between human APOBEC3G and HIV-1 Vif. These studies contribute to the growing knowledge of the APOBEC-Vif interaction and may help guide future efforts to disrupt this interaction as an antiviral therapy or exploit the interaction as a novel strategy to inhibit APOBEC3B-dependent tumor evolution. IMPORTANCE Primate APOBEC3 proteins provide innate immunity against retroviruses such as HIV and SIV. HIV-1, the primary cause of AIDS, utilizes its Vif protein to specifically counteract restrictive human APOBEC3 enzymes. SIVmac239 Vif exhibits a much wider range of anti-APOBEC3 activities that includes several rhesus macaque enzymes and extends to multiple proteins in the human APOBEC3 repertoire, including APOBEC3B. Understanding the molecular determinants of the interaction between SIVmac239 Vif and human APOBEC3B adds to existing knowledge on the APOBEC3-Vif interaction and has potential to shed light on what processes may have shaped Vif functionality over evolutionary time. An intimate understanding of this interaction may also lead to a novel cancer therapy because, for instance, creating a derivative of SIVmac239 Vif that specifically targets human APOBEC3B could be used to suppress tumor genomic DNA mutagenesis by this enzyme, slow ongoing tumor evolution, and help prevent poor clinical outcomes. [ABSTRACT FROM AUTHOR]

Published
2018
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27. Natural Polymorphisms in Human APOBEC3H and HIV-1 Vif Combine in Primary T Lymphocytes to Affect Viral G-to-A Mutation Levels and Infectivity

Author

Refsland, Eric W., primary, Hultquist, Judd F., additional, Luengas, Elizabeth M., additional, Ikeda, Terumasa, additional, Shaban, Nadine M., additional, Law, Emily K., additional, Brown, William L., additional, Reilly, Cavan, additional, Emerman, Michael, additional, and Harris, Reuben S., additional

Published
2014
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29. Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B

Author

Shi, Ke, Carpenter, Michael A, Banerjee, Surajit, Shaban, Nadine M, Kurahashi, Kayo, Salamango, Daniel J, McCann, Jennifer L, Starrett, Gabriel J, Duffy, Justin V, Demir, Özlem, Amaro, Rommie E, Harki, Daniel A, Harris, Reuben S, and Aihara, Hideki

Abstract

APOBEC-catalyzed cytosine-to-uracil deamination of single-stranded DNA (ssDNA) has beneficial functions in immunity and detrimental effects in cancer. APOBEC enzymes have intrinsic dinucleotide specificities that impart hallmark mutation signatures. Although numerous structures have been solved, mechanisms for global ssDNA recognition and local target-sequence selection remain unclear. Here we report crystal structures of human APOBEC3A and a chimera of human APOBEC3B and APOBEC3A bound to ssDNA at 3.1-Å and 1.7-Å resolution, respectively. These structures reveal a U-shaped DNA conformation, with the specificity-conferring −1 thymine flipped out and the target cytosine inserted deep into the zinc-coordinating active site pocket. The −1 thymine base fits into a groove between flexible loops and makes direct hydrogen bonds with the protein, accounting for the strong 5′-TC preference. These findings explain both conserved and unique properties among APOBEC family members, and they provide a basis for the rational design of inhibitors to impede the evolvability of viruses and tumors.

Published
2017
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32. APOBEC3F Determinants of HIV-1 Vif Sensitivity.

Author

Land, Allison M., Shaban, Nadine M., Evans, Leah, Hultquist, Judd F., Albin, John S., and Harris, Reuben S.

Subjects
*HIV infections, *ANTIVIRAL agents, *PROTEASOME inhibitors, *CHIMERISM, *HOST-virus relationships
Abstract

HIV-1 Vif counteracts restrictive APOBEC3 proteins by targeting them for proteasomal degradation. To determine the regions mediating sensitivity to Vif, we compared human APOBEC3F, which is HIV-1 Vif sensitive, with rhesus APOBEC3F, which is HIV-1 Vif resistant. Rhesus-human APOBEC3F chimeras and amino acid substitution mutants were tested for sensitivity to HIV-1 Vif. This approach identified the 3 and 4 helices of human APOBEC3F as important determinants of the interaction with HIV-1 Vif. [ABSTRACT FROM AUTHOR]

Published
2014
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33. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism.

Author

Shaban, Nadine M., Shi, Ke, Lauer, Kate V., Carpenter, Michael A., Richards, Christopher M., Salamango, Daniel, Wang, Jiayi, Lopresti, Michael W., Banerjee, Surajit, Levin-Klein, Rena, Brown, William L., Aihara, Hideki, and Harris, Reuben S.

Subjects
*CANCER genetics, *ANTIVIRAL agents, *DIMERIZATION, *GENETIC regulation, *MUTAGENESIS, *TRANSPOSONS
Abstract

Summary Human APOBEC3H and homologous single-stranded DNA cytosine deaminases are unique to mammals. These DNA-editing enzymes function in innate immunity by restricting the replication of viruses and transposons. APOBEC3H also contributes to cancer mutagenesis. Here, we address the fundamental nature of RNA in regulating human APOBEC3H activities. APOBEC3H co-purifies with RNA as an inactive protein, and RNase A treatment enables strong DNA deaminase activity. RNA-binding-defective mutants demonstrate clear separation of function by becoming DNA hypermutators. Biochemical and crystallographic data demonstrate a mechanism in which double-stranded RNA mediates enzyme dimerization. Additionally, APOBEC3H separation-of-function mutants show that RNA binding is required for cytoplasmic localization, packaging into HIV-1 particles, and antiviral activity. Overall, these results support a model in which structured RNA negatively regulates the potentially harmful DNA deamination activity of APOBEC3H while, at the same time, positively regulating its antiviral activity. [ABSTRACT FROM AUTHOR]

Published
2018
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