APOBEC3 Family of Genes

Key takeaways:
~ APOBEC3 is a family of enzymes that helps the body fight viral infections by causing mutations in viral DNA.
~ APOBEC3G specifically targets retroviruses by interfering with their reverse transcriptase.
~ APOBEC3-driven mutations can lead to viral variants and have been linked to about 22% of human viral species.
~ In cancer, APOBEC3 enzymes may contribute to mutations in cancer cells, particularly in virus-initiated cancers like cervical cancer.
~ Genetic variants in APOBEC3 affect viral response and the risk for certain types of cancer.

What is APOBEC3?

Throughout human history, we have constantly battled invisible pathogenic foes. Humans have sophisticated, built-in systems for fighting off viruses — this is how we have survived as a species.

One of the enzyme families involved in responding to viruses is called APOBEC3. It has a unique way of stopping viruses from replicating. Essentially, it causes mutations in the viral DNA, rendering the virus inactive. Once in a while, though, the mutations can increase the virulence of a virus.

Apolipoprotein B Editing Complex (APOBEC3) is a family of enzymes called cytidine deaminases, which play an important role in responding to viral infections.

The APOBEC3G gene encodes an enzyme that is a part of the innate defense mechanism against retroviral infections as well as a few other types of viruses.

Retroviruses insert their viral RNA into the genome of the host cell’s DNA to be transcribed. While typical viruses use the host’s cellular mechanisms to convert viral RNA into proteins, retroviruses do things differently and use reverse transcriptase to produce DNA from the viral RNA. That DNA is then incorporated into the host cell’s genome. (While this sounds pretty wild, we actually have a lot of old viral DNA in our human genome.)

Once the retrovirus is incorporated into the host cell’s nuclear DNA, the virus proteins can be transcribed and translated, just like our regular genes are transcribed and translated. The viral proteins then can assemble new copies of the virus.

Retroviruses include HIV, but HIV has evolved the Viral infectivity factor protein (Vif), which counteracts the effects of APOBEC3G.

APOBEC3G is also part of the defense mechanism against poxviruses such as the monkeypox virus and other DNA viruses that utilize reverse transcription.

Viruses that are acted upon by by members of the APOBEC3 family include:[ref][ref][ref]

• Human T-lymphotropic virus
• herpes simplex 1
• RSV
• mumps
• HPV
• measles
• Epstein-Barr virus

The APOBEC3 family of proteins also inhibits coronavirus infections, although the mechanism of action there is not yet determined.[ref]

Some researchers think that APOBEC3-driven mutations are causing most of the variation in the SARS-CoV-2 virus.[ref]

What does APOBEC3 do?

APOBEC3G interferes with reverse transcriptase by causing mutations in the creation of the viral DNA. Specifically, it causes mutations converting G (guanine) to A (adenine) in the viral DNA. The mutations then may cause the virus to not function or not replicate well.[ref]

While the mutations in the viral DNA caused by APOBEC3G can cause the virus to no longer be infectious, it can also sometimes cause mutations that still allow the virus to function, just differently than before. In other words, APOBEC3G can cause variants in a virus.

Overall, researchers found that approximately 22% of human viral species are shaped by APOBEC3-causing mutations that result in positive evolutionary pressure in the virus.[ref]

In addition to causing hypermutations in retroviruses, researchers think that APOBEC3G also inhibits viral replication by other means. Cell studies show that APOBEC3G can inhibit infection by parvoviruses without hypermutating their genomes.[ref]

Interferon is one of the first innate immune system signals produced in a viral infection. APOBEC3G is upregulated in response to interferon. It is also produced in T cells, B cells, and macrophages, and B cells can release it in exosomes.[ref]

APOBEC3 in cancer:

HPV (human papillomavirus) is the primary cause of cervical cancer. While most HPV infections are harmless and clear up spontaneously, persistent HPV infections can lead to cancer in certain circumstances. Recently, researchers discovered that women with cervical cancer had higher levels of APOBEC3G than women who had HPV without getting cancer.[ref]

Researchers think that APOBEC3s are causing mutations in cancer cells by wrongly targeting the cell genome in cancers initiated by viruses. One study explains: “For example, high-risk papillomaviruses, whose viral genomes carry an APOBEC3 footprint, indirectly promote cell transformation due to the sustained APOBEC3 mutagenic activity.”[ref]

Lifehacks:

There are tradeoffs as far as whether higher APOBEC3 levels are protective in viral replication or a negative in certain types of cancer. Keep in mind that not all cancers are the same, and always talk with your doctor if you have any questions about whether a supplement is right for you.

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