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PubMed1998

Immune receptor editing: revise and select.

Secondary antigen receptor gene recombination occurs in developing lymphocytes, and in more mature T and B cells. In the developing lymphocyte, "editing" occurs in response to receptor ligation by autoantigens. As a result of receptor editing, anti-self-reactive cells are converted to non-self-reactive cells, and self-reactive clones are thereby salvaged before negative selection. This antigen-induced change in the receptor specificity was not foreseen in the clonal selection theory. However, editing could be incorporated into the clonal selection theory by limiting receptor selection to a specific stage in lymphocyte development that precedes cellular selection as suggested by Jerne (1971). We know much less about the origin, regulation, or function of V(D)J recombination in mature lymphocytes. Nevertheless, antigen-induced receptor selection is likely to play an important role in shaping immune responses.

Animals↗
PubMed2025

Turbo-charging crop improvement: harnessing multiplex editing for polygenic trait engineering and beyond.

Multiplex CRISPR editing has emerged as a transformative platform for plant genome engineering, enabling the simultaneous targeting of multiple genes, regulatory elements, or chromosomal regions. This approach is effective for dissecting gene family functions, addressing genetic redundancy, engineering polygenic traits, and accelerating trait stacking and de novo domestication. Its applications now extend beyond standard gene knockouts to include epigenetic and transcriptional regulation, chromosomal engineering, and transgene-free editing. These capabilities are advancing crop improvement not only in annual species but also in more complex systems such as polyploids, undomesticated wild relatives, and species with long generation times. At the same time, multiplex editing presents technical challenges, including complex construct design and the need for robust, scalable mutation detection. We discuss current toolkits and recent innovations in vector architecture, such as promoter and scaffold engineering, that streamline workflows and enhance editing efficiency. High-throughput sequencing technologies, including long-read platforms, are improving the resolution of complex editing outcomes such as structural rearrangements-often missed by standard genotyping-when targeting repetitive or tandemly spaced loci. To fully realize the potential of multiplex genome engineering, there is growing demand for user-friendly, synthetic biology-compatible, and scalable computational workflows for gRNA design, construct assembly, and mutation analysis. Experimentally validated inducible or tissue-specific promoters are also highly desirable for achieving spatiotemporal control. As these tools continue to evolve, multiplex CRISPR editing is poised to become a foundational technology of next-generation crop improvement to address challenges in agriculture, sustainability, and climate resilience.

Gene Editing↗
PubMed1998

Interaction of mitochondrial RNA editing and nucleolytic processing in the restoration of male fertility in sorghum.

Nucleolytic processing of transcripts within mitochondrial orf107, associated with male sterility in sorghum, is regulated by the fertility restoration gene Rf3, conferring 75% cleavage of whole-length transcripts. Two transcript editing sites are 81% and 61% edited in rf3rf3 lines, while these sites are 41% and 10% edited in the remaining whole-length transcripts in an Rf3Rf3 line. RNA editing and processing efficiency in F1 progeny were similar to the Rf3Rf3 parent, and analyses of backcross progeny indicated that all rf3rf3 lines were characterized by high editing efficiency. We postulate that highly edited transcripts within the population are quickly processed in lines carrying Rf3, generating a residual population of poorly edited transcripts. Thus, action of Rf3 may have no direct affect on RNA editing, and may be dependent on a substrate of highly edited transcripts. These data indicate a potentially novel role of RNA editing in gene expression through an influence on the efficiency of transcript processing.

Amino Acid Sequence↗
PubMed1993

RNA editing in Newcastle disease virus.

The co-transcriptional editing of the Newcastle disease virus (NDV) P gene has been studied by sequence analysis of cloned viral genomic RNA and mRNA. Evidence has been obtained for the specific insertion of non-templated G nucleotides, the consequence of which is the generation of three populations of P gene-derived mRNAs. The three populations encode proteins (P, V and W) which have a common N-terminal region, but which utilize three different reading frames at their C termini. Paradoxically, NDV edits its P gene mRNA by the insertion of non-templated G residues in a manner similar to Sendai and measles viruses (P-->V editing) despite its apparent closer evolutionary relationship to the simian virus type 5, mumps and related group of viruses which edit a V genomic sequence to generate an mRNA to encode a functional P protein (V-->P editing).

Amino Acid Sequence↗
PubMed1989

Apolipoprotein B48 RNA editing in chimeric apolipoprotein EB mRNA.

Apolipoprotein (apo) B occurs in two forms, apoB100 (512 kDa) and apoB48 (240 kDa); both are derived from the same gene. A novel mechanism involving editing of the apoB mRNA causes the formation of apoB48; the first base of codon 2153 is changed from cytosine to uracil, converting a glutamine codon to a premature stop codon. To identify the apoB mRNA sequence elements recognized by the apoB mRNA editing mechanism, two apoB cDNA fragments (354 and 63 base pairs) with codon 2153 near their centers were inserted into a high expression vector of another secreted apolipoprotein, apoE. The resulting vectors, pHEB-354 and -63, were transfected into Chinese hamster ovary cells, HepG2 cells, and apoB48-producing CaCo-2 cells. The secreted chimeric apolipoproteins (apoEB354 and apoEB63) were analyzed for premature truncation, and the mRNA was analyzed for the presence of an edited base. The pHEB-354 construct produced a truncated protein only in CaCo-2 cells, whereas pHEB-63 produced no truncated protein in any of the three cell types. The mRNA was converted to cDNA and amplified by the polymerase chain reaction technique. Differential hybridization of the polymerase chain reaction products with CAA (Gln) and TAA (Stop) specific probes detected an edited base only in cDNA from CaCo-2 cells transfected with pHEB-354, in agreement with the protein analysis. We conclude that the nucleotide sequence of the apoB cDNA insert in pHEB-354 contains sufficient information to be edited in CaCo-2 cells. In these cells, a cryptic polyadenylation site was activated in the edited pHEB-354 mRNA. As a result, CaCo-2 cells transfected with pHEB-354 produced a short, edited pHEB-354 mRNA and a long, unedited pHEB-354 mRNA. Chinese hamster ovary cells transfected with pHEB-354 or CaCo-2 cells transfected with pHEB-63 produced only a full length transcript. Amplification of the pHEB-354 cDNA using 3'-primers upstream and downstream of the poly(A) addition site and hybridization with the TAA probe confirmed these results. This unusual mRNA editing apparently occurs before polyadenylation, probably in the nucleus.

Adenocarcinoma↗
PubMed1998

RNA editing in gymnosperms and its impact on the evolution of the mitochondrial coxI gene.

Sequence analysis of the mitochondrial coxI gene in eight gymnosperm species revealed a high rate of nonsynonymous nucleotide substitutions with a strong (98%) predominance of C-T substitutions. Further analysis of the corresponding coxI cDNA sequences showed that all the non-synonymous C-T changes in the coxI genomic DNA sequences were eliminated by RNA editing resulting in nearly identical mRNA (amino acid) sequences among the species. Pronounced variation in the number and location of edited sites was found among species. Most species had a relatively large number of edited sites (from 25 to 34). However, no RNA editing of the coxI sequence was found in Gingko biloba or Larix sibirica. The sequence composition of the investigated coxI fragment suggests that the coxI gene in G. biloba and L. sibirica originated from edited mitochondrial coxI transcripts by reverse transcription followed by insertion into the nuclear genome or back into the mitochondrial genome. Our results also demonstrate that where there are a large number of edited sites, RNA editing can accelerate the divergence of nucleotide sequences among species.

Amino Acid Sequence↗
PubMed1999

Two nucleotides immediately upstream of the essential A6G3 slippery sequence modulate the pattern of G insertions during Sendai virus mRNA editing.

Editing of paramyxovirus P gene mRNAs occurs cotranscriptionally and functions to fuse an alternate downstream open reading frame to the N-terminal half of the P protein. G residues are inserted into a short G run contained within a larger purine run (AnGn) in this process, by a mechanism whereby the transcribing polymerase stutters (i.e., reads the same template cytosine more than once). Although Sendai virus (SeV) and bovine parainfluenza virus type 3 (bPIV3) are closely related, the G insertions in their P mRNAs are distributed differently. SeV predominantly inserts a single G residue within the G run of the sequence 5' AACAAAAAAGGG, whereas bPIV3 inserts one to six G's at roughly equal frequency within the sequence 5' AUUAAAAAAGGGG (differences are underlined). We have examined how the cis-acting editing sequence determines the number of G's inserted, both in a transfected cell system using minigenome analogues and by generating recombinant viruses. We found that the presence of four rather than three G's in the purine run did not affect the distribution of G insertions. However, when the underlined AC of the SeV sequence was replaced by the UU found in bPIV3, the editing phenotype from both the minigenome and the recombinant virus resembled that found in natural bPIV3 infections (i.e., a significant fraction of the mRNAs contained two to six G insertions). The two nucleotides located just upstream of the polypurine tract are thus key determinants of the editing phenotype of these viruses. Moreover, the minimum number of A residues that will promote SeV editing phenotype is six but can be reduced to five when the upstream AC is replaced by UU. A model for how the upstream dinucleotide controls the insertion phenotype is presented.

Base Sequence↗
PubMed2026

A translational framework for early-phase inner-ear gene therapy: clinical trial design, regulatory strategy, and ethical considerations.

PURPOSE OF REVIEW: Hereditary hearing loss has historically been approached as a diagnostic category rather than a therapeutically modifiable disease. Recent advances in molecular genetics, cochlear gene delivery, and first-in-human clinical trials are changing that. This review summarizes contemporary progress in the genetics of hearing loss, with emphasis on emerging gene-based therapies, clinical trial design, regulatory and ethical considerations, and practical implications for otolaryngologists as biologic treatment enters clinical practice. RECENT FINDINGS: Early clinical trials targeting OTOF -related DFNB9 deafness have demonstrated satisfactory safety profiles and meaningful auditory recovery, establishing the first proof-of-concept for cochlear gene therapy in humans, culminating in the April 2026 FDA approval of Otarmeni. Genetic diagnoses are increasingly informing prognosis, cochlear implant counseling, and therapeutic candidacy. Preclinical research continues to expand toward recessive, dominant, and syndromic hearing loss using gene replacement, antisense, RNA interference, and genome-editing strategies. Substantial challenges remain, including heterogeneous outcome measures, uncertain long-term efficacy, regulatory complexity, and inequitable global access. SUMMARY: The genetics of hearing loss is transitioning from a diagnostic modality to an interventional one. Widespread clinical impact will require advances in vector engineering, equitable implementation, multidisciplinary counseling, and integration with established rehabilitation pathways. For otolaryngologists, genetic literacy is becoming essential to contemporary hearing care.

Humans↗
PubMed2024

SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution.

CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.

Humans↗
PubMed2006

G-InforBIO: integrated system for microbial genomics.

BACKGROUND: Genome databases contain diverse kinds of information, including gene annotations and nucleotide and amino acid sequences. It is not easy to integrate such information for genomic study. There are few tools for integrated analyses of genomic data, therefore, we developed software that enables users to handle, manipulate, and analyze genome data with a variety of sequence analysis programs. RESULTS: The G-InforBIO system is a novel tool for genome data management and sequence analysis. The system can import genome data encoded as eXtensible Markup Language documents as formatted text documents, including annotations and sequences, from DNA Data Bank of Japan and GenBank encoded as flat files. The genome database is constructed automatically after importing, and the database can be exported as documents formatted with eXtensible Markup Language or tab-deliminated text. Users can retrieve data from the database by keyword searches, edit annotation data of genes, and process data with G-InforBIO. In addition, information in the G-InforBIO database can be analyzed seamlessly with nine different software programs, including programs for clustering and homology analyses. CONCLUSION: The G-InforBIO system simplifies genome analyses by integrating several available software programs to allow efficient handling and manipulation of genome data. G-InforBIO is freely available from the download site.

Algorithms↗
PubMed2003

Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1.

ADAR1 (adenosine deaminase acting on RNA-1) is widely expressed in mammals, but its biological role is unknown. We show here by gene targeting that ADAR1 selectively edits in vivo two of five closely spaced adenosines in the serotonin 5-hydroxytryptamine subtype 2C receptor pre-mRNA of nervous tissue; and hence, site-selective adenosine-to-inosine editing is indeed a function of ADAR1. Remarkably, homozygosity for two different null alleles of ADAR1 caused a consistent embryonic phenotype appearing early at embryonic day 11 and leading to death between embryonic days 11.5 and 12.5. This phenotype manifests a rapidly disintegrating liver structure, along with severe defects in definitive hematopoiesis, encompassing both erythroid and myeloid/granuloid progenitors as well as spleen colony-forming activity from the aorta-gonad-mesonephros region and fetal liver. Probably as a consequence of these developmental impairments, ADAR1-deficient embryonic stem cells failed to contribute to liver, bone marrow, spleen, thymus, and blood in adult chimeric mice. Thus, ADAR1 subserves critical steps in developing non-nervous tissue, which are likely to include transcript editing.

Adenosine Deaminase↗
PubMed1992

An in vitro system for the editing of ATP synthase subunit 9 mRNA using wheat mitochondrial extracts.

A posttranscriptional modification (C-to-U) at specific positions of plant mitochondrial mRNA leads to changes in the amino acid sequence as well as to the emergence of novel initiation or termination sites. This phenomenon, named RNA editing, has been described for several mitochondrial genes from different plant sources. We have found recently that RNA editing of the ATP synthase subunit 9 (atp9) mRNA involves eight changes including the creation of a new stop codon. In this article, we describe an in vitro system devised to follow the editing of wheat mitochondrial atp9 mRNA. Nonedited mRNA was obtained to serve as substrate for this reaction by in vitro transcription of the corresponding gene with T7 RNA polymerase. The source of conversion factor(s) was a soluble fraction obtained from purified wheat mitochondria lysed with salt and detergent. Edited RNA molecules were detected by hybridization with an end-labeled synthetic oligodeoxynucleotide probe complementary to a short region containing four editing events. Optimal conditions for the in vitro RNA editing reaction were determined. The reaction is sensitive to high temperature and protease digestion. Pretreatment with micrococcal nuclease decreased RNA editing activity in the mitochondrial extract, suggesting that a nucleic acid is necessary for the enzymatic reactions. Analysis of the edited mRNA showed that the in vitro reaction led to the same products as those observed in vivo.

Amino Acid Sequence↗
PubMed1995

Pervasive migration of organellar DNA to the nucleus in plants.

A surprisingly large number of plant nuclear DNA sequences inferred to be remnants of chloroplast and mitochondrial DNA migration events were detected through computer-assisted database searches. Nineteen independent organellar DNA insertions, with a median size of 117 bp (range of 38 to > 785 bp), occur in the proximity of 15 nuclear genes. One fragment appears to have been passed through a RNA intermediate, based on the presence of an edited version of the mitochondrial gene in the nucleus. Tandemly arranged fragments from disparate regions of organellar genomes and from different organellar genomes indicate that the fragments joined together from an intracellular pool of RNA and/or DNA before they integrated into the nuclear genome. Comparisons of integrated sequences to genes lacking the insertions, as well as the occurrence of coligated fragments, support a model of random integration by end joining. All transferred sequences were found in noncoding regions, but the positioning of organellar-derived DNA in introns, as well as regions 5' and 3' to nuclear genes, suggests that the random integration of organellar DNA has the potential to influence gene expression patterns. A semiquantitative estimate was performed on the amount of organellar DNA being transferred and assimilated into the nucleus. Based on this database survey, we estimate that 3-7% of the plant nuclear genomic sequence files contain organellar-derived DNA. The timing and the magnitude of genetic flux to the nuclear genome suggest that random integration is a substantial and ongoing process for creating sequence variation.

Base Sequence↗
PubMed2025

In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.

Homology-directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested Repair Drive, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene, fumarylacetoacetate hydrolase (Fah), and delivering an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild-type mice up to 25%, which resulted in a fivefold increased expression of a therapeutic transgene, human factor IX (FIX). Repair Drive was well tolerated and did not induce toxicity or tumorigenesis during a 1-year follow-up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.

Animals↗
PubMed1995

RNA editing of a group II intron in Oenothera as a prerequisite for splicing.

The trans-splicing group II intron c/d in the Oenothera mitochondrial nad1 gene is modified by RNA editing in domain 6. This C-to-U conversion generates the typical domain 6 structure, which prompted us to speculate that this RNA editing event might be essential for splicing. To test this hypothesis, we investigated the influence of unedited and edited sequences of the Oenothera intron on splicing in vitro. The stem of domain 6 of intron nad1-c/d was transplanted into the autocatalytic yeast intron aI5c, yielding chimeras with the genomic C and the edited U, respectively, 5' of the branchpoint A. When incubated under self-splicing conditions, only the edited chimera was released as a lariat, while the precursor with the genomically coded C remained inactive. Our results support the hypothesis that Oenothera group II intron nad1-c/d cannot be spliced from the primary transcript without previous editing in domain 6.

Base Sequence↗
PubMed1993

RNA editing in kinetoplastid mitochondria.

RNA editing in the mitochondrion of kinetoplastid protozoa results in the posttranscriptional addition and deletion of uridine residues in mRNAs. Editing of mRNAs can lead to the formation of initiation codons for mitochondrial translation, the correction of frame-shifted genes at the RNA level, and in extensively edited mRNAs, the formation of complete reading frames. Kinetoplastid RNA editing requires that genetic information from two or more separately transcribed genes be brought together to form the mature, edited mRNA. The information necessary for the proper insertion or deletion of uridines in the mRNA is present in small mitochondrial transcripts termed guide RNAs (gRNAs). Editing of mRNAs appears to be associated with a high molecular weight complex, called the editosome, containing specific gRNAs, unedited mRNAs, and proteins. Editing is likely a two-step process involving first the breakage of a phosphodiester bond at the editing site and formation of a chimeric molecule with a gRNA covalently joined to the 5' end of the 3' portion of an mRNA. The chimera is resolved by the rejoining of the 5' end of the mRNA to the 3' portion of the mRNA with the addition or deletion of a uridine at the junction point. Two models are proposed for the biochemical mechanism of RNA editing. The first is an enzymatic cascade of cleavage and ligation while the other supports successive rounds of transesterification. The obvious functional necessity for editing in kinetoplastid mitochondria is the formation of translatable mRNAs. Far less clear is the evolutionary origin of editing and the role editing plays in regulating mitochondrial gene expression.

Animals↗
PubMed1995

Tissue-specific, developmental and nutritional regulation of the gene encoding the catalytic subunit of the rat apolipoprotein B mRNA editing enzyme: functional role in the modulation of apoB mRNA editing.

Apolipoprotein B (apoB) mRNA editing, a posttranscriptional site-specific cytidine deamination reaction, is mediated by a protein complex of which the catalytic component (REPR) has recently been cloned. REPR mRNA was demonstrated by RNase protection at highest abundance in small intestine and colon but the transcript was detectable in all tissues examined including kidney, spleen, lung, liver, and ovary. ApoB mRNA was found predominantly in the liver and small intestine but low levels were detected in all adult tissues examined and found to be variably (29-86% TAA) edited. In addition, S100 extracts prepared from spleen and kidney were competent to edit an apoB RNA template in vitro, suggesting that the entire apoB mRNA editing complex is present and functionally active in these tissues. In situ hybridization demonstrated REPR mRNA to be distributed along the entire villus-crypt axis, while apoB mRNA distribution did not extend into the crypts. In the liver, both apoB and REPR mRNA were detected in all cells of the hepatic lobule without an apparent gradient of expression. REPR mRNA was found in the red pulp of the spleen and in the superficial crypt cells of the colon. This distribution of REPR mRNA was recapitulated by immunocytochemical localization of the protein within these tissues. Finally, the developmental and nutritional modulation of REPR was examined in relation to endogenous apoB mRNA editing. Small intestinal apoB mRNA editing was found to undergo a developmentally regulated increase beginning at gestational day 20, preceding a developmental increase in REPR mRNA abundance. Additionally, hepatic and kidney apoB mRNA editing both revealed a temporal dissociation from alterations in REPR mRNA abundance. By contrast, adult rats subjected to fasting and refeeding a high carbohydrate diet, demonstrated concordant modulation of endogenous apoB mRNA editing and REPR mRNA abundance (r = 0.92, P < 0.001). Taken together, the data demonstrate that REPR and other components of the rat apoB mRNA editing complex are widely distributed and undergo distinct developmental and metabolic regulation that interact to regulate apoB mRNA editing in a tissue-specific manner.

APOBEC-1 Deaminase↗
PubMed1991

RNA-mediated transfer of the gene coxII from the mitochondrion to the nucleus during flowering plant evolution.

The gene coxII, normally present in the mitochondrion, was functionally transferred to the nucleus during flowering plant evolution. coxII transfer is estimated to have occurred between 60 and 200 million years ago, whereas loss of coxII from the mitochondrion occurred much more recently, being restricted to a single genus of legumes. Most legumes have coxII in both the nucleus and the mitochondrion; however, no evidence is found for simultaneous coxII expression in both compartments. The nuclear coxII sequence more closely resembles edited mitochondrial coxII transcripts than the genes encoding these RNAs. Hence, gene transfer appears to have involved reverse transcription of an edited RNA intermediate. The nuclear gene contains an intron at the junction of the transit peptide sequence and the mature protein-coding sequence; exon shuffling may have played a role in assembling a functional coxII gene in the nucleus.

Amino Acid Sequence↗