Diversification of AID/APOBEC-like deaminases in metazoa: multiplicity of clades and widespread roles in immunity

Krishnan, Arunkumar; Iyer, Lakshminarayan M.; Holland, Stephen J.; Boehm, Thomas; Aravind, L.

doi:10.1073/pnas.1720897115

Cited by 65 publications

(85 citation statements)

References 74 publications

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“…The APOBEC3 family of AID paralogues also restrict viral infection by deaminating viral genomes; UNG2 and APE activities downstream of APOBEC3 can contribute to viral restriction (49,50). AID/APOBEC-like deaminases occur across metazoa, dictyosteliida, and even algae, and may have evolved in an arms race with viruses and retro elements (51). Here, we've shown that SAMHD1 is another virus restriction factor that contributes to the mutagenicity of AID-by promoting transversion mutation downstream of AID.…”

Section: Similarities Between Ig Hypermutation and Intracellular Virumentioning

confidence: 81%

SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation

Thientosapol

Bosnjak

Durack

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced deaminase (AID) initiates hypermutation of genes in activated B cells by converting C:G into U:G base pairs. G-phase variants of uracil base excision repair (BER) and mismatch repair (MMR) then deploy translesion polymerases including REV1 and Pol η, which exacerbates mutation. dNTP paucity may contribute to hypermutation, because dNTP levels are reduced in G phase to inhibit viral replication. To derestrict G-phase dNTP supply, we CRISPR-inactivated SAMHD1 (which degrades dNTPs) in germinal center B cells. inactivation increased B cell virus susceptibility, increased transition mutations at C:G base pairs, and substantially decreased transversion mutations at A:T and C:G base pairs in both strands. We conclude that SAMHD1's restriction of dNTP supply enhances AID's mutagenicity and that the evolution of hypermutation included the repurposing of antiviral mechanisms based on dNTP starvation.

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Section: Similarities Between Ig Hypermutation and Intracellular Virumentioning

confidence: 81%

SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation

Thientosapol

Bosnjak

Durack

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Some of these have predicted signal peptides suggesting that they are secreted (e.g., in Caenorhabditis remanei and Entamoeba). The combination of lineagespecific expansions, rapid evolution, and secretion is a hallmark of proteins that are deployed as effectors in defensive or offensive roles in biological conflicts (Krishnan et al 2018;Zhang et al 2016;Lespinet et al 2002). In light of this we hypothesize that several eukaryotic Smr proteins, 12 290 295 300 305 310 especially the expanded versions, might function beyond translation surveillance as effectors deployed against viral or parasitic RNA.…”

Section: Evolution Of Nonu-1 and Smr-domain Proteinsmentioning

confidence: 99%

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

Glover

Burroughs

Egelhofer

et al. 2019

Preprint

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Cellular translation surveillance rescues ribosomes that stall on problematic mRNAs. During translation surveillance, endonucleolytic cleavage of the problematic mRNA is a critical step in rescuing stalled ribosomes. However, the nuclease(s) responsible remain unknown. Here we identify NONU-1 as a novel endoribonuclease required for translation surveillance pathways including No-Go and Nonstop mRNA Decay. We show that: (1) NONU-1 reduces Nonstop and No-Go mRNA levels; (2) NONU-1 contains an Smr RNase domain required for mRNA decay and with properties similar to the unknown endonuclease; and (3) the domain architecture and catalytic residues of NONU-1 are conserved throughout metazoans and eukaryotes, respectively. We extend our results in C. elegans to homologous factors in S. cerevisiae, showing conservation of function of the NONU-1 protein across billions of years of evolution.Our work establishes the identity of a previously unknown factor critical to translation surveillance and will inform mechanistic studies at the intersection of translation and mRNA decay. 1 5 10 15 20 25 2 30 35 40 45 50 that organism. NONU-1 contains a conserved IF3-C fold domain previously implicated in processing RNA. Our results identify a critical new component of the translation surveillance machinery in two model organisms and suggest why this factor has been recalcitrant to discovery in S. cerevisiae. RESULTS nonu-1 encodes a novel factor required for Nonstop mRNA DecayWe previously developed a phenotypic reporter in C. elegans that allowed us to identify Nonstop mRNA Decay factors via reverse and forward genetics ( Figure 1A, (Arribere and Fire 2018)).Briefly, the reporter was constructed using the unc-54 locus as expression and function of this gene has been extensively studied (Brenner 1974;Epstein et al. 1974;Dibb et al. 1985Dibb et al. , 1989Moerman et al. 1982;Bejsovec and Anderson 1988;Anderson and Brenner 1984) and unc-54 has been used in previous suppressor screens (Hodgkin et al. 1989). To construct a Nonstop reporter at the unc-54 locus we first integrated a GFP at the C-terminus of UNC-54 by CRISPR/Cas9. We also removed all stop codons from the 3'UTR and integrated a ribosomal skipping T2A sequence between the C-terminal GFP and the remainder of the 3'UTR. The T2A sequence is a viral-derived peptide that cotranslationally releases the upstream protein and allows UNC-54::GFP to escape Nonstop protein decay (so-called "Ribosome Quality Control", (Bengtson and Joazeiro 2010;Shao et al. 2013;Shen et al. 2015)). We hereafter refer to the unc-54::gfp::t2a::nonstop reporter as unc-54 (Nonstop). Animals with the unc-54 (Nonstop) reporter deficient in Nonstop mRNA Decay exhibit derepression of the locus, as evidenced by increased GFP fluorescence, mRNA expression, and egg laying (unc-54 encodes a muscle myosin required in the vulva for egg laying) ( Figure 1B, (Arribere and Fire 2018)).Although our initial screen successfully identified C. elegans' skih-2 and ttc-37 (homologs of S. cerevisiae SKI2 and SKI3, respectively), ...

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“…RNA editing refers to specific modifications in an RNA molecule that result in alterations of the RNA sequence compared to the one encoded by the genome. RNA editing events occur in all eukaryotes, although the molecular mechanisms are taxon dependent and may involve different enzymes, leading to different RNA modifications, particularly between plants and animals [25,26]. For instance, substitutional RNA editing is a mechanism occurring across all metazoans, and this process is characterized by nucleotide modification mediated by deaminases of, principally, two distinct families.…”

Section: Editing Of Mirnamentioning

confidence: 99%

Deciphering miRNAs’ Action through miRNA Editing

Sousa

Gjorgjieva

Dolicka

et al. 2019

IJMS

601

343

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MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called "RNA editing" involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA's stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA's ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

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Diversification of AID/APOBEC-like deaminases in metazoa: multiplicity of clades and widespread roles in immunity

Cited by 65 publications

References 74 publications

SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation

SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation

NONU-1 encodes a conserved endonuclease required for mRNA translation surveillance

Deciphering miRNAs’ Action through miRNA Editing

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