Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

Abstract

Proteins of the AID/APOBEC family are capable of cytidine deamination in nucleic acids forming uracil. These enzymes are involved in mRNA editing, protection against viruses, the introduction of point mutations into DNA during somatic hypermutation, and antibody isotype switching. Since these deaminases, especially AID, are potent mutagens, their expression, activity, and specificity are regulated by several intracellular mechanisms. In this review, we discuss the mechanisms of impaired expression and activation of AID/APOBEC proteins in human tumors and their role in carcinogenesis and tumor progression. Also, the diagnostic and potential therapeutic value of increased expression of AID/APOBEC in different types of tumors is analyzed. We assume that in the case of solid tumors, increased expression of endogenous deaminases can serve as a marker of response to immunotherapy since multiple point mutations in host DNA could lead to amino acid substitutions in tumor proteins and thereby increase the frequency of neoepitopes.

Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line

“…1A), the trinucleotide context of C>G mutations (Fig. 6B) is consistent with preferences of AID/APOBEC cytosine deaminases, which are known DNA mutators ( 58 , 59 ). C>T mutations in these peaks are strongly elevated in a CpG context (Fig.…”

“…( B ) Same as (A), but for the off-center peaks in X chromosome hotspots. The trinucleotide context of C>G changes resembles the preferences of the AID/APOBEC family, particularly AID, APOBEC3F, and APOBEC3G ( 58 , 59 ). APOBEC3F is strongly expressed in human testes ( 59 ).…”

Potential HIV/ART-mediated germline mutations causing congenital inborn errors of immunity in children born to HIV+ couples: an alarming spectre

“…A3 proteins are involved in protection from viral infections. Five of them (A3C, A3G, A3D, A3F and A3H) are of interest for protection from HIV, and are packaged into HIV virions [3]. The viral accessory protein Vif is known to bind and cause degradation of APOBECs.…”

“…The family comprises 11 members: AID, A1, A2, A3A-D, A3F-H and A4. They bind RNA and/or ssDNA and deaminase cytidine and/or deoxycytidine by recognizing short sequence motifs (reviewed in [2,3]). Of these, AID and A2 only bind ssDNA, A3A and A1 bind both ssDNA and RNA, and A3G binds only RNA.…”

“…Importantly, they could also cause collateral damage by targeting a cellular DNA inducing hypermutations and chromosomal translocations. These off target effects are well known for causing somatic mutations in cancers [3]. Recent studies have shown that several A3 proteins to be expressed in the nucleus, albeit at lower levels than cytoplasm [4] and hence have access to nuclear DNA.…”