Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA

• Published in: The Journal of biological chemistry 2007-04, Vol.282 (16), p.11667-11675
• Main Authors: Yang, Bin, Chen, Keyang, Zhang, Chune, Huang, Sophia, Zhang, Hui
• Format: Article
• Language: English
• Subjects: APOBEC-3G Deaminase; Base Sequence; Catalysis; Cell Line; Cytidine Deaminase; DNA Glycosylases - metabolism; DNA Glycosylases - physiology; DNA, Viral - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism; Gene Products, vif - metabolism; HIV-1 - metabolism; Human immunodeficiency virus 1; Humans; Molecular Sequence Data; Mutation; Nucleoside Deaminases - metabolism; Plasmids - metabolism; Repressor Proteins - metabolism; Retrovirus; RNA, Small Interfering - metabolism; vif Gene Products, Human Immunodeficiency Virus; Virion - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M606864200

Cellular cytidine deaminases APOBEC3 family is a group of potent inhibitors for many exogenous and endogenous retroviruses. It has been demonstrated that they induce G to A hypermutations in the nascent retroviral DNA, resulting from the cytosine (C) to uracil (U) conversions in minus-stranded viral DNA. In this report, we have demonstrated that the result of C to U conversion in minus-stranded DNA of human immunodeficiency virus type 1 (HIV-1) could trigger a degradation of nascent viral DNA mediated by uracil DNA glycosylases-2 (UNG2) and apurinic/apyrimidinic endonuclease (APE). Since antiviral activity of APOBEC3G is partially affected by UNG2 inhibitor Ugi or UNG2-specific short-interfering RNA in virus-producing cells but not target cells, the virion-associated UNG2 most likely mediates this process. Interestingly, as APE-specific short-interfering RNA can also partially inhibit the anti-HIV-1 activity of APOBEC3G in virus-producing cells but not in target cells and APE molecules can be detected within HIV-1 virions, it seems that the required APE is also virion-associated. Furthermore, the in vitro cleavage experiment using uracil-containing single-stranded DNA as a template has demonstrated that the uracil-excising catalytic activity of virion-associated UNG2 can remove dU from the uracil-containing viral DNA and leave an abasic site, which could be further cleaved by virion-associated APE. Based upon our observations, we propose that the degradation of APOBEC3G-edited viral DNA mediated by virion-associated UNG2 and APE during or after reverse transcription could be partially responsible for the potent anti-HIV-1 effect by APOBEC3G in the absence of vif.