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Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination

Nature Reviews Genetics volume 23, pages 505–518 (2022)Cite this article

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Abstract

The AID/APOBEC polynucleotide cytidine deaminases have historically been classified as either DNA mutators or RNA editors based on their first identified nucleic acid substrate preference. DNA mutators can generate functional diversity at antibody genes but also cause genomic instability in cancer. RNA editors can generate informational diversity in the transcriptome of innate immune cells, and of cancer cells. Members of both classes can act as antiviral restriction factors. Recent structural work has illuminated differences and similarities between AID/APOBEC enzymes that can catalyse DNA mutation, RNA editing or both, suggesting that the strict functional classification of members of this family should be reconsidered. As many of these enzymes have been employed for targeted genome (or transcriptome) editing, a more holistic understanding will help improve the design of therapeutically relevant programmable base editors.

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Fig. 1: Physiological and aberrant functions of the AID/APOBEC deaminases.
Fig. 2: The emergence of the AID/APOBEC family and the conserved core cytidine deaminase domain.
Fig. 3: Structural insights from generalists and specialists.
Fig. 4: The consequences of deamination for adaptive evolution.
Fig. 5: APOBEC-derived DNA and RNA base-editing tools.

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Acknowledgements

Work on RNA editing and modification in the Papavasiliou laboratory is funded by the European Research Council (ERC) (#649019) and the German Research Foundation (DFG) (TRR319-RMaP and SPP1784). The authors thank all members, past and present, of the Papavasiliou laboratory for discussions, and sincerely apologize to the many colleagues whose work could not be cited for reasons of space.

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Authors and Affiliations

  1. Division of Immune Diversity (D150), Program in Cancer Immunology, German Cancer Research Centre (DKFZ), Heidelberg, Germany

    Riccardo Pecori, Salvatore Di Giorgio, J. Paulo Lorenzo & F. Nina Papavasiliou

  2. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany

    J. Paulo Lorenzo & F. Nina Papavasiliou

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  1. Riccardo Pecori
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  2. Salvatore Di Giorgio
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  3. J. Paulo Lorenzo
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  4. F. Nina Papavasiliou
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All authors researched data for the article, made substantial contributions to discussions of the content, and wrote the article. F.N.P. and R.P. edited the manuscript and drafted the final submission.

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Correspondence to F. Nina Papavasiliou.

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Glossary

Base modifications

Chemically altered nucleotides within mature RNA molecules.

dCasRx

Catalytically dead RNA-guided RNA-targeting CasRx from Ruminococcus flavefaciens XPD3002. CasRx is another member of the CRISPR family (class 2, VI-D).

dPspCas13b

Catalytically dead RNA-guided RNA-targeting CRISPR–Cas13b from Prevotella sp. P5-125. Cas13b is a member of the CRISPR family (class 2, type VI). Physiologically, Cas13b catalyses site-specific cleavage of single-stranded RNA.

G-quadruplex

A non-canonical four-stranded secondary structure of guanine-rich DNA sequences.

Guide RNAs

(gRNAs). Short RNA sequences used in base-editing technologies to target the base editor to a specific sequence in DNA or RNA. Depending on the tagging system used, the base editor can be recruited by the gRNA using specific scaffolds (for Cas proteins), sequences (MS2 coat protein) or chemical modifications (for SNAP).

Intrinsically disordered region

(IDR). An unstructured domain of proteins that are believed to have roles in intermolecular and intramolecular interactions, such as complex formation and phase separation.

MS2-tagged

Refers to a molecule labelled using a tagging system based on the natural interaction between the MS2 bacteriophage coat protein and a stem–loop structure from the phage genome. The sequence forming the stem–loop can be attached to a guide RNA (gRNA) to target an MS2-tagged base editor.

Nuclear export signal

(NES). A short peptide motif enriched for hydrophobic residues (such as Leu) recognized by exportins (such as XPO1/CRM1) that tags a protein for nuclear exit.

Nuclear localization signal

(NLS). A short peptide motif enriched for positively charged residues that tags a protein for nuclear import.

Pseudotyped HIV

Chimaeric viruses composed of the envelope glycoprotein of vesicular stomatis virus (VSV-G) and the human immunodeficiency virus type 1 (HIV-1) core; these viruses are more infectious than non-pseudotyped HIV-1 viruses.

SNAP-tagged

Refers to a molecule labelled using a tagging system based on the SNAP-tag self-labelling protein derived from the human O6-alkylguanine-DNA alkyltransferase. As a SNAP-tag will form a covalent linkage with benzylguanine (BG)-modified nucleotides, a SNAP-tagged base editor can be directed to specific targets by BG-modified guide RNAs (gRNAs).

Stem–loops

Specific structures that may occur in single-stranded RNA (ssRNA) when complementary sequences base pair to form a double helix that ends in an unpaired (single-stranded) loop. Stem–loops are also known as hairpin structures or hairpin loops.

π-Stacking

Attractive non-covalent interactions between aromatic rings.

Tumour restriction

The limitation of tumour growth and/or tumour suppression or ablation by numerous distinct molecular mechanisms. Here, we specifically refer to the limitation of tumour growth owing to cell death after activation-induced cytidine deaminase/apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (AID/APOBEC)-mediated hypermutation.

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Pecori, R., Di Giorgio, S., Paulo Lorenzo, J. et al. Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination. Nat Rev Genet 23, 505–518 (2022). https://doi.org/10.1038/s41576-022-00459-8

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