Molecular Mechanism for Regulating APOBEC3G DNA Editing Function by the Non-catalytic Domain

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 10

PMID 39389938

Authors

Hanjing Yang

Josue Pacheco

Kyumin Kim

Ayub Bokani

Fumiaki Ito

Diako Ebrahimi

Xiaojiang S Chen

Affiliations

Soon will be listed here.

Abstract

APOBEC3G, part of the AID/APOBEC cytidine deaminase family, is crucial for antiviral immunity. It has two zinc-coordinated cytidine-deaminase domains. The non-catalytic N-terminal domain strongly binds to nucleic acids, whereas the C-terminal domain catalyzes C-to-U editing in single-stranded DNA. The interplay between the two domains is not fully understood. Here, we show that DNA editing function of rhesus macaque APOBEC3G on linear and hairpin loop DNA is enhanced by AA or GA dinucleotide motifs present downstream in the 3'-direction of the target-C editing sites. The effective distance between AA/GA and the target-C sites is contingent on the local DNA secondary structure. We present two co-crystal structures of rhesus macaque APOBEC3G bound to ssDNA containing AA and GA, revealing the contribution of the non-catalytic domain in capturing AA/GA DNA. Our findings elucidate the molecular mechanism of APOBEC3G's cooperative function, which is critical for its antiviral role and its contribution to mutations in cancer genomes.

Citing Articles

Leong S, Nasser H, Ikeda T Int J Mol Sci. 2025; 26(4).

PMID: 40004025 PMC: 11855278. DOI: 10.3390/ijms26041561.

References

Sheehy A, Gaddis N, Choi J, Malim M . Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002; 418(6898):646-50. DOI: 10.1038/nature00939. View

Lecossier D, Bouchonnet F, Clavel F, Hance A . Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science. 2003; 300(5622):1112. DOI: 10.1126/science.1083338. View

Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D . Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature. 2003; 424(6944):99-103. DOI: 10.1038/nature01709. View

Zhang H, Yang B, Pomerantz R, Zhang C, Arunachalam S, Gao L . The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature. 2003; 424(6944):94-8. PMC: 1350966. DOI: 10.1038/nature01707. View

Yu Q, Konig R, Pillai S, Chiles K, Kearney M, Palmer S . Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol. 2004; 11(5):435-42. DOI: 10.1038/nsmb758. View

Suspene R, Sommer P, Henry M, Ferris S, Guetard D, Pochet S . APOBEC3G is a single-stranded DNA cytidine deaminase and functions independently of HIV reverse transcriptase. Nucleic Acids Res. 2004; 32(8):2421-9. PMC: 419444. DOI: 10.1093/nar/gkh554. View

Holtz C, Sadler H, Mansky L . APOBEC3G cytosine deamination hotspots are defined by both sequence context and single-stranded DNA secondary structure. Nucleic Acids Res. 2013; 41(12):6139-48. PMC: 3695494. DOI: 10.1093/nar/gkt246. View

Cuevas J, Geller R, Garijo R, Lopez-Aldeguer J, Sanjuan R . Extremely High Mutation Rate of HIV-1 In Vivo. PLoS Biol. 2015; 13(9):e1002251. PMC: 4574155. DOI: 10.1371/journal.pbio.1002251. View

Browne E, Allers C, Landau N . Restriction of HIV-1 by APOBEC3G is cytidine deaminase-dependent. Virology. 2009; 387(2):313-21. PMC: 3708462. DOI: 10.1016/j.virol.2009.02.026. View

10.

Conticello S, Harris R, Neuberger M . The Vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G. Curr Biol. 2003; 13(22):2009-13. DOI: 10.1016/j.cub.2003.10.034. View

11.

Newman E, Holmes R, Craig H, Klein K, Lingappa J, Malim M . Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Curr Biol. 2005; 15(2):166-70. DOI: 10.1016/j.cub.2004.12.068. View

12.

Guo F, Cen S, Niu M, Saadatmand J, Kleiman L . Inhibition of tRNA₃(Lys)-primed reverse transcription by human APOBEC3G during human immunodeficiency virus type 1 replication. J Virol. 2006; 80(23):11710-22. PMC: 1642613. DOI: 10.1128/JVI.01038-06. View

13.

Iwatani Y, Chan D, Wang F, Stewart-Maynard K, Sugiura W, Gronenborn A . Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Res. 2007; 35(21):7096-108. PMC: 2175344. DOI: 10.1093/nar/gkm750. View

14.

Bishop K, Verma M, Kim E, Wolinsky S, Malim M . APOBEC3G inhibits elongation of HIV-1 reverse transcripts. PLoS Pathog. 2008; 4(12):e1000231. PMC: 2584787. DOI: 10.1371/journal.ppat.1000231. View

15.

Wang X, Ao Z, Chen L, Kobinger G, Peng J, Yao X . The cellular antiviral protein APOBEC3G interacts with HIV-1 reverse transcriptase and inhibits its function during viral replication. J Virol. 2012; 86(7):3777-86. PMC: 3302496. DOI: 10.1128/JVI.06594-11. View

16.

Gillick K, Pollpeter D, Phalora P, Kim E, Wolinsky S, Malim M . Suppression of HIV-1 infection by APOBEC3 proteins in primary human CD4(+) T cells is associated with inhibition of processive reverse transcription as well as excessive cytidine deamination. J Virol. 2012; 87(3):1508-17. PMC: 3554184. DOI: 10.1128/JVI.02587-12. View

17.

Pollpeter D, Parsons M, Sobala A, Coxhead S, Lang R, Bruns A . Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G. Nat Microbiol. 2017; 3(2):220-233. PMC: 6014619. DOI: 10.1038/s41564-017-0063-9. View

18.

Olson M, Harris R, Harki D . APOBEC Enzymes as Targets for Virus and Cancer Therapy. Cell Chem Biol. 2017; 25(1):36-49. PMC: 5775913. DOI: 10.1016/j.chembiol.2017.10.007. View

19.

Green A, Weitzman M . The spectrum of APOBEC3 activity: From anti-viral agents to anti-cancer opportunities. DNA Repair (Amst). 2019; 83:102700. PMC: 6876854. DOI: 10.1016/j.dnarep.2019.102700. View

20.

Ito J, Gifford R, Sato K . Retroviruses drive the rapid evolution of mammalian genes. Proc Natl Acad Sci U S A. 2019; 117(1):610-618. PMC: 6955324. DOI: 10.1073/pnas.1914183116. View