APOBEC

A mechanism of generating protein diversity is mRNA editing. The APOBEC family of proteins perform mRNA modifications by deaminating cytidine bases to uracil. The N-terminal domain of APOBEC-like proteins is the catalytic domain, while the C-terminal domain is a pseudocatalytic domain. More specifically, the catalytic domain is a zinc dependent cytidine deaminase domain and is essential for cytidine deamination. The positively charged zinc ion in the catalytic domain attracts to the partial-negative charge of RNA.

In the case of APOBEC-1, the mRNA transcript of intestinal apolipoprotein B is altered. RNA editing by APOBEC-1 requires homodimerization and this complex interacts with RNA-binding proteins to form the editosome.{{cite journal | vauthors = Wedekind JE, Dance GS, Sowden MP, Smith HC | title = Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business | journal = Trends in Genetics | volume = 19 | issue = 4 | pages = 207–216 | date = April 2003 | pmid = 12683974 | doi = 10.1016/S0168-9525(03)00054-4 }} The resulting structure interacts with the codon CAA at codon 2153 and deaminates it into UAA, producing a stop codon that results in mRNA that is translated into the intestinal apoB-48 isoform.{{cite web|url=https://www.omim.org/entry/600130|title=APOLIPOPROTEIN B mRNA-EDITING ENZYME, CATALYTIC POLYPEPTIDE 1; APOBEC1|website=Online Mendelian Inheritance in Man|vauthors=McKusick VA, Hamosh A|date=19 December 2019|orig-date=Originally published 27 September 1994|access-date=23 December 2023}} For other APOBEC-modified transcripts such as in the site-specific deamination of a CGA to a UGA stop codon in neurofibromatosis type 1 (NF1) mRNA, the resulting proteins are predicted to be truncated as well, although these transcripts are possibly degraded.{{cite journal | vauthors = Blanc V, Davidson NO | title = C-to-U RNA editing: mechanisms leading to genetic diversity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 3 | pages = 1395–1398 | date = January 2003 | pmid = 12446660 | doi = 10.1074/jbc.r200024200 | doi-access = free }}

C-to-U modifications do not always result in the truncation of proteins. For example, in humans/mammals they help protect from viral infections.{{cite journal | vauthors = Cervantes-Gracia K, Gramalla-Schmitz A, Weischedel J, Chahwan R | title = APOBECs orchestrate genomic and epigenomic editing across health and disease | journal = Trends in Genetics | volume = 37 | issue = 11 | pages = 1028–1043 | date = November 2021 | pmid = 34353635 | doi = 10.1016/j.tig.2021.07.003 | s2cid = 236934922 | doi-access = free }} APOBEC family proteins are widely expressed in cells of the human innate immune system.{{cite journal | vauthors = Koito A, Ikeda T | title = Intrinsic immunity against retrotransposons by APOBEC cytidine deaminases | journal = Frontiers in Microbiology | volume = 4 | pages = 28 | date = 2013 | pmid = 23431045 | pmc = 3576619 | doi = 10.3389/fmicb.2013.00028 | doi-access = free }}

These enzymes, when misregulated, are a major source of mutation in numerous cancer types.{{cite web |url=http://www.genengnews.com/gen-news-highlights/unexpected-dna-binding-mechanism-suggests-ways-to-block-enzyme-activity-in-cancer/81253584 |title=Unexpected DNA-Binding Mechanism Suggests Ways to Block Enzyme Activity in Cancer |date=Dec 2016 |quote=Based on ("Structural Basis for Targeted DNA Cytosine Deamination and Mutagenesis by APOBEC3A and APOBEC3B") online in Nature Structural and Molecular Biology. }}{{cite journal | vauthors = Butler K, Banday AR | title = APOBEC3-mediated mutagenesis in cancer: causes, clinical significance and therapeutic potential | journal = Journal of Hematology & Oncology | volume = 16 | issue = 1 | pages = 31 | date = March 2023 | pmid = 36978147 | pmc = 10044795 | doi = 10.1186/s13045-023-01425-5 | doi-access = free }} When the expression of APOBEC family proteins is triggered, accidental mutations in somatic cells can lead to the development of oncogenes, cells which have the potential to develop into a tumor. APOBEC proteins are further expressed in attempt to regulate tumor formation. This makes APOBEC proteins a helpful marker for diagnosing malignant tumors.{{cite book | vauthors = Okazaki IM, Kotani A, Honjo T | title = AID for Immunoglobulin Diversity | chapter = Role of AID in tumorigenesis | series = Advances in Immunology | volume = 94 | pages = 245–273 | date = 2007-01-01 | pmid = 17560277 | doi = 10.1016/s0065-2776(06)94008-5 | publisher = Academic Press | isbn = 9780123737069 }}

A 2013 review discussed the structural and biophysical aspects of APOBEC3 family enzymes.{{cite journal | vauthors = Vasudevan AA, Smits SH, Höppner A, Häussinger D, Koenig BW, Münk C | title = Structural features of antiviral DNA cytidine deaminases | journal = Biological Chemistry | volume = 394 | issue = 11 | pages = 1357–1370 | date = November 2013 | pmid = 23787464 | doi = 10.1515/hsz-2013-0165 | s2cid = 4151961 | url = http://juser.fz-juelich.de/record/139785/files/FZJ-2013-05757.pdf }} Many of the APOBEC protein features are described in the widely studied APOBEC3G's page.{{tone inline|date=June 2022}}

Human genes encoding members of the APOBEC protein family include:

• APOBEC1
• APOBEC2
• APOBEC3A
• APOBEC3B
• APOBEC3C
• APOBEC3D ("APOBEC3E" now refers to this)
• APOBEC3F
• APOBEC3G
• APOBEC3H
• APOBEC4
• Activation-induced (cytidine) deaminase (AID)

{{Reflist}}

• Gupta, A., Gazzo, A., Selenica, P. et al., APOBEC3 mutagenesis drives therapy resistance in breast cancer, Nature Genetics (April 1, 2025) {{doi|10.1038/s41588-025-02187-1}}

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Category:EC 3.5.4