Structural highlightsFunctionABC3H_HUMAN DNA deaminase (cytidine deaminase) which acts as an inhibitor of retrovirus replication and retrotransposon mobility via deaminase-dependent and -independent mechanisms (PubMed:16571802, PubMed:16920826, PubMed:18779051, PubMed:18827027, PubMed:20062055, PubMed:22915799, PubMed:29290613). The A3H-var/haplotype 2 exhibits antiviral activity against vif-deficient HIV-1 (PubMed:18299330, PubMed:21835787, PubMed:23097438, PubMed:29290613). After the penetration of retroviral nucleocapsids into target cells of infection and the initiation of reverse transcription, it can induce the conversion of cytosine to uracil in the minus-sense single-strand viral DNA, leading to G-to-A hypermutations in the subsequent plus-strand viral DNA (PubMed:18299330). The resultant detrimental levels of mutations in the proviral genome, along with a deamination-independent mechanism that works prior to the proviral integration, together exert efficient antiretroviral effects in infected target cells (PubMed:18299330). Selectively targets single-stranded DNA and does not deaminate double-stranded DNA or single- or double-stranded RNA (PubMed:20062055). Exhibits antiviral activity also against T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons (PubMed:20062055, PubMed:22457529).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
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.
The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism.,Shaban NM, Shi K, Lauer KV, Carpenter MA, Richards CM, Salamango D, Wang J, Lopresti MW, Banerjee S, Levin-Klein R, Brown WL, Aihara H, Harris RS Mol Cell. 2018 Jan 4;69(1):75-86.e9. doi: 10.1016/j.molcel.2017.12.010. Epub 2017, Dec 28. PMID:29290613[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See AlsoReferences
- ↑ OhAinle M, Kerns JA, Malik HS, Emerman M. Adaptive evolution and antiviral activity of the conserved mammalian cytidine deaminase APOBEC3H. J Virol. 2006 Apr;80(8):3853-62. PMID:16571802 doi:10.1128/JVI.80.8.3853-3862.2006
- ↑ Dang Y, Wang X, Esselman WJ, Zheng YH. Identification of APOBEC3DE as another antiretroviral factor from the human APOBEC family. J Virol. 2006 Nov;80(21):10522-33. PMID:16920826 doi:10.1128/JVI.01123-06
- ↑ Dang Y, Siew LM, Wang X, Han Y, Lampen R, Zheng YH. Human cytidine deaminase APOBEC3H restricts HIV-1 replication. J Biol Chem. 2008 Apr 25;283(17):11606-14. PMID:18299330 doi:10.1074/jbc.M707586200
- ↑ OhAinle M, Kerns JA, Li MM, Malik HS, Emerman M. Antiretroelement activity of APOBEC3H was lost twice in recent human evolution. Cell Host Microbe. 2008 Sep 11;4(3):249-59. PMID:18779051 doi:10.1016/j.chom.2008.07.005
- ↑ Tan L, Sarkis PT, Wang T, Tian C, Yu XF. Sole copy of Z2-type human cytidine deaminase APOBEC3H has inhibitory activity against retrotransposons and HIV-1. FASEB J. 2009 Jan;23(1):279-87. PMID:18827027 doi:10.1096/fj.07-088781
- ↑ Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol. 2010 Feb;17(2):222-9. doi: 10.1038/nsmb.1744. Epub 2010 Jan , 10. PMID:20062055 doi:10.1038/nsmb.1744
- ↑ Hultquist JF, Lengyel JA, Refsland EW, LaRue RS, Lackey L, Brown WL, Harris RS. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J Virol. 2011 Nov;85(21):11220-34. doi: 10.1128/JVI.05238-11. Epub 2011 Aug 10. PMID:21835787 doi:10.1128/JVI.05238-11
- ↑ Ooms M, Krikoni A, Kress AK, Simon V, Munk C. APOBEC3A, APOBEC3B, and APOBEC3H haplotype 2 restrict human T-lymphotropic virus type 1. J Virol. 2012 Jun;86(11):6097-108. doi: 10.1128/JVI.06570-11. Epub 2012 Mar 28. PMID:22457529 doi:10.1128/JVI.06570-11
- ↑ Phalora PK, Sherer NM, Wolinsky SM, Swanson CM, Malim MH. HIV-1 replication and APOBEC3 antiviral activity are not regulated by P bodies. J Virol. 2012 Nov;86(21):11712-24. doi: 10.1128/JVI.00595-12. Epub 2012 Aug 22. PMID:22915799 doi:10.1128/JVI.00595-12
- ↑ Chaipan C, Smith JL, Hu WS, Pathak VK. APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. J Virol. 2013 Jan;87(1):444-53. doi: 10.1128/JVI.00676-12. Epub 2012 Oct 24. PMID:23097438 doi:10.1128/JVI.00676-12
- ↑ Shaban NM, Shi K, Lauer KV, Carpenter MA, Richards CM, Salamango D, Wang J, Lopresti MW, Banerjee S, Levin-Klein R, Brown WL, Aihara H, Harris RS. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol Cell. 2018 Jan 4;69(1):75-86.e9. doi: 10.1016/j.molcel.2017.12.010. Epub 2017, Dec 28. PMID:29290613 doi:http://dx.doi.org/10.1016/j.molcel.2017.12.010
- ↑ Shaban NM, Shi K, Lauer KV, Carpenter MA, Richards CM, Salamango D, Wang J, Lopresti MW, Banerjee S, Levin-Klein R, Brown WL, Aihara H, Harris RS. The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol Cell. 2018 Jan 4;69(1):75-86.e9. doi: 10.1016/j.molcel.2017.12.010. Epub 2017, Dec 28. PMID:29290613 doi:http://dx.doi.org/10.1016/j.molcel.2017.12.010
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