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   Home  »  Epigenetic Resources  »  APOBEC3 Cytidine Deaminases: Viral Restriction and Cancer Therapy 
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APOBEC3 Cytidine Deaminases: Viral Restriction and Cancer Therapy

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The APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) protein superfamily plays an important role in nucleic acid editing and immunity.  Eleven APOBEC proteins are encoded by the human genome: APOBEC1 (A1), APOBEC2 (A2), APOBEC3 (consisting of the subfamily members A3A, A3B, A3C, A3D, A3F, A3G, and A3H), APOBEC4 (A4), and AID (activation-induced cytidine deaminase).  They serve as cytidine deaminases and can catalyze deamination of cytidines to uridines in both DNA and RNA.  While APOBECs perform essential protective functions by restricting viruses and mobile genomic elements, as well as regulating immunoglobulin maturity/diversity, their overexpression or misregulation can promote carcinogenesis.

Of particular interest is the A3 subfamily due to their well-known antiviral activity.  APOBEC3-mediated cytidine deamination of single-strand viral DNA results in G-to-A hypermutations during subsequent complementary strand synthesis, consequently rendering the virus replication-defective.  Hypermutations induced by A3 enzymes have been found to inhibit retrotransposons, retroviruses like HIV-1, and DNA viruses such as AAV, HBV, HSVs, and HPV [1-12].  APOBEC3A is unique in that, in addition to catalyzing C-to-U substitutions, it is the only A3 subfamily member that can efficiently deaminate 5-methylcytidine to thymidine, thereby facilitating the cellular clearance of methylated exogenous DNA [13-15].

While APOBEC3 enzymes are generally not expressed in healthy tissue, abnormal expression levels, particularly for A3A and A3B, are detected in approximately 50% of tumors [16-18].  These expression levels have been correlated with APOBEC3-specific mutational signatures in multiple cancers: lung, breast, bladder, cervical, and ovarian, among others [16,17,19,20].  By exploiting the genomic instability and ensuing DNA damage response (DDR) activated by APOBEC3 expression, apoptosis and cell death in A3-expressing cancer cells were induced via DDR inhibition [20,21].  Therefore, quantitative measures of APOBEC3 activity in tumors are critical for the research and development of candidate inhibitors for cancer therapy.

Regarding the current COVID-19 pandemic and the emergence of new and highly infectious variants, evidence suggests cytosine deamination as a major driving force behind the evolution of the SARS-CoV-2 coronavirus [22].  The extensive C-to-U substitutions displayed by the SARS-CoV-2 genome indeed may infer an underlying APOBEC3-driven mechanism.  Interestingly, APOBEC3A mRNA has been reported among the most abundant transcripts to be identified in COVID-19 patients [23].  Detection of APOBEC3/A enzyme activity and inhibition would thus be of great benefit in virus infection control, cancer diagnostics, and the development of novel target-based anti-viral and anti-cancer therapeutics.

To this end, EpigenTek developed and offers the Epigenase™ APOBEC3 Cytidine Deaminase Activity/Inhibition Assay Kit (catalog no. P-3140) and Epigenase™ APOBEC3A Activity/Inhibition Assay Kit (catalog no. P-3142).  Activity/Inhibition of total APOBEC3 enzymes or APOBEC3A enzyme can be conveniently assessed with these rapid colorimetric assays in only 4-5 hours, using cell extracts or purified enzymes as input material.  An assay standard is provided in each kit for the quantification of enzyme activity.  The innovative kit compositions enable background signals to be extremely low, allowing the assays to be simple, accurate, reliable, and consistent.

References:
  1. Sheehy AM, et. al. (2002) Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 418(6898):646-50.
  2. Mangeat B, et. al. (2003). Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature. 424(6944):99-103.
  3. Zheng YH, et. al. (2004). Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication. J Virol. 78(11):6073-6.
  4. Dang Y, et. al. (2008). Human cytidine deaminase APOBEC3H restricts HIV-1 replication. J Biol Chem. 2008 Apr 25;283(17):11606-14.
  5. Dang Y, Wang X, Esselman WJ, Zheng YH. (2006) Identification of APOBEC3DE as another antiretroviral factor from the human APOBEC family. J Virol. 80(21):10522-33.
  6. Bogerd HP, et. al. (2006). APOBEC3A and APOBEC3B are potent inhibitors of LTR-retrotransposon function in human cells. Nucleic Acids Res. 34(1):89-95.
  7. Muckenfuss H, et. al. (2006).  APOBEC3 proteins inhibit human LINE-1 retrotransposition. J Biol Chem. 281(31):22161-22172.
  8. Chen H, et. al. (2006).  APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 16(5):480-5.
  9. Janahi EM, McGarvey MJ. (2013). The inhibition of hepatitis B virus by APOBEC cytidine deaminases. J Viral Hepat. 20(12):821-8.
  10. Vieira VC, et. al. (2014). Human papillomavirus E6 triggers upregulation of the antiviral and cancer genomic DNA deaminase APOBEC3B. mBio. 5(6)
  11. Wang Z, et. al. (2014). APOBEC3 deaminases induce hypermutation in human papillomavirus 16 DNA upon beta interferon stimulation. J Virol. 88(2):1308-17.
  12. Suspène R, et. al. (2011).  Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J Virol. 85(15):7594-602.
  13. Wijesinghe P, Bhagwat AS. (2012). Efficient deamination of 5-methylcytosines in DNA by human APOBEC3A, but not by AID or APOBEC3G. Nucleic Acids Res. 40(18):9206-17.
  14. Suspène R, et. al. (2013). Efficient deamination of 5-methylcytidine and 5-substituted cytidine residues in DNA by human APOBEC3A cytidine deaminase. PLoS One. 8(6):e63461.
  15. Carpenter MA, et. al. (2012). Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme APOBEC3A. J Biol Chem. 287(41):34801-8.
  16. Swanton C, et. al. (2015). APOBEC Enzymes: Mutagenic Fuel for Cancer Evolution and Heterogeneity. Cancer Discov. 5(7):704-12.
  17. Buisson R, et. al. (2019). Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science. 2019 Jun 28;364(6447)
  18. Burns MB, et. al. (2013) APOBEC3B is an enzymatic source of mutation in breast cancer. Nature. 494(7437):366-70.
  19. Lawrence MS, et. al. (2013). Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 499(7457):214-218.
  20. Buisson R, et. al. (2017). APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition. Cancer Res. 77(17):4567-4578.
  21. Green AM, et. al. (2017). Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint. Cancer Res. 77(17):4579-4588.
  22. Matyášek R, Kovařík A. (2020). Mutation Patterns of Human SARS-CoV-2 and Bat RaTG13 Coronavirus Genomes Are Strongly Biased Towards C>U Transitions, Indicating Rapid Evolution in Their Hosts. Genes (Basel). 11(7):761.
  23. Blanco-Melo D, et. al. (2020). Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 181(5):1036-1045


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