Alternative titles; symbols
HGNC Approved Gene Symbol: APOBEC1
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:7,649,400-7,670,599 (from NCBI)
Apolipoprotein B, a major protein component of circulating plasma lipoproteins, exists in 2 forms: apoB-100 and apoB-48. In humans, apoB-100 is synthesized in the liver and is present in very low density lipoproteins and their metabolic products. On the other hand, apoB-48 is synthesized in the small intestine and is the form of apoB present in chylomicrons and chylomicron remnants. The biogenesis of apoB-48 is unique in that apoB-100 and apoB-48 are products of the same gene, APOB (107730). ApoB-48 mRNA is produced from apoB-100 mRNA by RNA editing. A C-to-U conversion of the first base of codon 2153, which encodes glutamine, changes it from CAA to UAA, an in-frame stop codon (Hodges and Scott, 1992; Chan, 1993). ApoB-48 contains 2,152 amino acids, compared to 4,536 residues in apoB-100. The apolipoprotein B mRNA-editing protein (APOBEC1) is involved in the production of apoB-48 from apoB-100.
Lau et al. (1994) used a cloned rat cDNA as a probe to identify the cDNA and genomic sequences of the human APOBEC1 gene. By Northern blot analysis, they showed that the human editing protein mRNA is expressed exclusively in the small intestine. The cDNA sequence predicts a translation product of 236 amino acids. The editing protein is a cytidine deaminase showing structural homology to some known mammalian and bacteriophage deoxycytidylate deaminases.
Hadjiagapiou et al. (1994) likewise isolated from human jejunum a cDNA that mediates in vitro editing of a synthetic apoB RNA template upon complementation with chicken intestinal extracts. The cDNA specified a 236-residue protein that is 69% identical to the apoB mRNA editing protein cloned from rat small intestine.
By PCR analysis, Hirano et al. (1997) demonstrated an exon 2-skipped form of APOBEC1 mRNA that arises through use of an alternative splice acceptor. This alternative splicing causes a frameshift that produces a novel 36-amino acid peptide. The exon 2-skipped form accounts for approximately 50% of mRNA in the adult small intestine and up to 90% of APOBEC1 mRNA in the developing gut. An antipeptide antibody identified the truncated protein in the villus cells of the adult small intestine.
Lau et al. (1994) showed that expression of the human APOBEC1 cDNA in HepG2 cells resulted in editing of the intracellular apoB mRNA.
Chan (1994) stated that no diseases related to the mutation in the APOBEC1 gene were known or surmised at that time. It was not known if apoB-100 can substitute for apoB-48 in chylomicron production by the small intestine. Therefore, it was unclear whether deficiency or defect of the editing protein, which was predicted to cause the intestinal production of apoB-100 in place of apoB-48, was associated with any readily recognizable phenotype. Chan (1994) noted that it is possible that APOB mRNA is not the only RNA edited by the editing protein. The editing protein by itself is inactive against synthetic APOB mRNA in vitro. Editing requires the addition of 1 or more complementing proteins, which at the time of the Chan (1994) report had not been purified or cloned. These proteins are present in multiple tissues including those that do not express apoB or the editing protein. There is conjecture that these complementing proteins determine the specificity of the editing protein such that with one set of proteins the editing protein edits APOB mRNA and with another set of proteins it edits some other, as yet unknown, RNA.
BEDP is a 27-kD protein (p27) with homology to cytidine deaminase. Navaratnam et al. (1995) showed that it is a zinc-containing deaminase that operates catalytically like the E. coli enzyme that acts on monomeric substrates (Betts et al., 1994). In contrast with this bacterial enzyme, which does not bind RNA, BEDP interacts with its polymeric APOB mRNA substrate at AU sequences adjacent to the editing site. This interaction is necessary for editing. Certain mutations that inactivate the enzyme did not affect RNA binding. Thus, they found that RNA binding did not require a catalytically active site. The authors speculated that the acquisition of polymeric substrate binding provided a route for the evolution of this editing enzyme from one that acts on monomeric substrates. Oka et al. (1997) found that active APOBEC1 functions as a dimer.
Mukhopadhyay et al. (2002) demonstrated that the APOBEC1 gene is involved in C-to-U editing of NF1 (613113) mRNA. Thus, its role extends beyond that of intestinal apoB RNA. The NF1 studies were performed in peripheral nerve sheath tumor samples from patients with neurofibromatosis I (162200).
Harris et al. (2002) showed that APOBEC1 and its homologs APOBEC3C (607750) and APOBEC3G (607113) exhibited potent DNA mutator activity in an E. coli assay. These proteins appeared to trigger DNA mutation through dC deamination, and each protein exhibited a distinct local target sequence specificity. The results revealed the existence of a family of potential active dC/dG mutators, with possible implications for cancer.
TET1 (607790) is a methylcytosine dioxygenase that initiates the modifications of methylated cytosines that are required for cytosine demethylation and gene activation. Using overexpression and knockdown studies and in vitro and in vivo techniques, Guo et al. (2011) found that several cytidine deaminases, including AID (AIDCA; 605257) and APOBEC family members, functioned with TET1 to reduce cytosine methylation and activate gene transcription in a base excision-mediated pathway of active DNA methylation.
Roberts et al. (2013) showed that throughout cancer genomes, APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome datasets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas, revealed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2 (ERBB2; 164870)-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. Roberts et al. (2013) concluded that the APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.
Hirano et al. (1997) found that the APOBEC1 gene spans 18 kb and contains 5 exons, all of which are translated. Transcription initiation is localized to a single start site 34-bp upstream of the open reading frame in exon 1.
By FISH, Lau et al. (1994) localized the human APOBEC1 gene to 12p13.2-p13.1. Espinosa et al. (1994) also mapped the human APOBEC1 gene to 12p13.1 by FISH.
Grunewald et al. (2019) showed that a CRISPR-Cas cytosine base editor (CBE) with rat APOBEC1 can cause extensive transcriptomewide deamination of RNA cytosines in human cells, inducing tens of thousands of C-to-U edits with frequencies ranging from 0.07% to 100% in 38 to 58% of expressed genes. CBE-induced RNA edits occurred in both protein-coding and non-protein-coding sequences and generated missense, nonsense, splice site, and 5-prime and 3-prime UTR mutations. Grunewald et al. (2019) engineered 2 CBE variants bearing mutations in rat APOBEC1 that substantially decreased the number of RNA edits (by more than 390-fold and more than 3,800-fold) in human cells. These variants also showed more precise on-target DNA editing than the wildtype CBEs and, for most guide RNAs tested, no substantial reduction in editing efficiency. Finally, Grunewald et al. (2019) showed that an adenine base editor can also induce transcriptomewide RNA edits. Grunewald et al. (2019) concluded that their results had implications for the use of base editors in both research and clinical settings, illustrated the feasibility of engineering improved variants with reduced RNA editing activities, and suggested the need to more fully define and characterize the RNA off-target effects of deaminase enzymes in base editor platforms.
Morrison et al. (1996) noted that the cytidine-to-uridine (C-to-U) editing of RNA is found in diverse animals and plants. It is most widespread in the mitochondria and chloroplasts of vascular plants, where RNA editing is necessary to produce viable mRNAs. In marsupials, it affects tRNA in the mitochondria. The subtle changes in RNA sequence resulting from RNA editing effect dramatic changes in biologic function. In transgenic mice and rabbits expressing abnormally high levels of APOBEC1, Yamanaka et al. (1995) noted reduced concentrations of apo-B100 and LDL but, unexpectedly, all of the animals developed liver dysplasia and many of the mice developed hepatocellular carcinomas. The authors also noted inappropriate editing of mRNAs other than apo-B and postulated that this might explain the tumorigenesis. Morrison et al. (1996) studied the opposite situation, deficiency of the editing protein. Mice were created with a null mutation of Apobec1 using homologous recombination in embryonic stem cells. Mice homozygous for this mutation were viable and made apo-B100 but not apo-B48. The null animals were fertile, and a variety of histologic, behavioral, and morphologic analyses revealed no phenotype other than abnormalities in lipoprotein metabolism, which included an increased low density lipoprotein fraction and a reduction in high density lipoprotein cholesterol. These studies demonstrated that neither the editing enzyme nor apo-B48 is essential for viability and suggested that the major role of the editing enzyme may be confined to the modulation of lipid transport.
Betts, L., Xiang, S., Short, S. A., Wolfenden, R., Carter, C. W., Jr. Cytidine deaminase: the 2.3 angstrom crystal structure of an enzyme: transition-state analog complex. J. Molec. Biol. 235: 635-656, 1994. [PubMed: 8289286] [Full Text: https://doi.org/10.1006/jmbi.1994.1018]
Chan, L. RNA editing: exploring one mode with apolipoprotein B mRNA. BioEssays 15: 33-41, 1993. [PubMed: 8466474] [Full Text: https://doi.org/10.1002/bies.950150106]
Chan, L. Personal Communication. Houston, Tex. 9/27/1994.
Espinosa, R., III, Funahashi, T., Hadjiagapiou, C., Le Beau, M. M., Davidson, N. O. Assignment of the gene encoding the human apolipoprotein B mRNA editing enzyme (APOBEC1) to chromosome 12p13.1. Genomics 24: 414-415, 1994. [PubMed: 7698776] [Full Text: https://doi.org/10.1006/geno.1994.1645]
Grunewald, J., Zhou, R., Garcia, S. P., Iyer, S., Lareau, C. A., Aryee, M. J., Joung, J. K. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors. Nature 569: 433-437, 2019. [PubMed: 30995674] [Full Text: https://doi.org/10.1038/s41586-019-1161-z]
Guo, J. U., Su, Y., Zhong, C., Ming, G.-I., Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145: 423-434, 2011. [PubMed: 21496894] [Full Text: https://doi.org/10.1016/j.cell.2011.03.022]
Hadjiagapiou, C., Giannoni, F., Funahashi, T., Skarosi, S. F., Davidson, N. O. Molecular cloning of a human small intestinal apolipoprotein B mRNA editing protein. Nucleic Acids Res. 22: 1874-1879, 1994. [PubMed: 8208612] [Full Text: https://doi.org/10.1093/nar/22.10.1874]
Harris, R. S., Petersen-Mahrt, S. K., Neuberger, M. S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Molec. Cell 10: 1247-1253, 2002. [PubMed: 12453430] [Full Text: https://doi.org/10.1016/s1097-2765(02)00742-6]
Hirano, K.-I., Min, J., Funahashi, T., Baunoch, D. A., Davidson, N. O. Characterization of the human apobec-1 gene: expression in gastrointestinal tissues determined by alternative splicing with production of a novel truncated peptide. J. Lipid Res. 38: 847-859, 1997. [PubMed: 9186903]
Hodges, P., Scott, J. Apolipoprotein B mRNA editing: a new tier for the control of gene expression. Trends Biochem. Sci. 17: 77-81, 1992. [PubMed: 1373530] [Full Text: https://doi.org/10.1016/0968-0004(92)90506-5]
Lau, P. P., Zhu, H.-J., Baldini, A., Charnsangavej, C., Chan, L. Dimeric structure of a human apolipoprotein B mRNA editing protein and cloning and chromosomal localization of its gene. Proc. Nat. Acad. Sci. 91: 8522-8526, 1994. [PubMed: 8078915] [Full Text: https://doi.org/10.1073/pnas.91.18.8522]
Morrison, J. R., Paszty, C., Stevens, M. E., Hughes, S. D., Forte, T., Scott, J., Rubin, E. M. Apolipoprotein B RNA editing enzyme-deficient mice are viable despite alterations in lipoprotein metabolism. Proc. Nat. Acad. Sci. 93: 7154-7159, 1996. [PubMed: 8692961] [Full Text: https://doi.org/10.1073/pnas.93.14.7154]
Mukhopadhyay, D., Anant, S., Lee, R. M., Kennedy, S., Viskochil, D., Davidson, N. O. C-U editing of neurofibromatosis 1 mRNA occurs in tumors that express both the type II transcript and apobec-1, the catalytic subunit of the apolipoprotein B mRNA-editing enzyme. Am. J. Hum. Genet. 70: 38-50, 2002. [PubMed: 11727199] [Full Text: https://doi.org/10.1086/337952]
Navaratnam, N., Bhattacharya, S., Fujino, T., Patel, D., Jarmuz, A. L., Scott, J. Evolutionary origins of apoB mRNA editing: catalysis by a cytidine deaminase that has acquired a novel RNA-binding motif at its active site. Cell 81: 187-195, 1995. [PubMed: 7736571] [Full Text: https://doi.org/10.1016/0092-8674(95)90328-3]
Oka, K., Kobayashi, K., Sullivan, M., Martinez, J., Teng, B.-B., Ishimura-Oka, K., Chan, L. Tissue-specific inhibition of apolipoprotein B mRNA editing in the liver by adenovirus-mediated transfer of a dominant negative mutant APOBEC-1 leads to increased low density lipoprotein in mice. J. Biol. Chem. 272: 1456-1460, 1997. [PubMed: 8999814] [Full Text: https://doi.org/10.1074/jbc.272.3.1456]
Roberts, S. A., Lawrence, M. S., Klimczak, L. J., Grimm, S. A., Fargo, D., Stojanov, P., Kiezun, A., Kryukov, G. V., Carter, S. L., Saksena, G., Harris, S., Shah, R. R., Resnick, M. A., Getz, G., Gordenin, D. A. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genet. 45: 970-976, 2013. [PubMed: 23852170] [Full Text: https://doi.org/10.1038/ng.2702]
Yamanaka, S., Balestra, M. E., Ferrell, L. D., Fan, J., Arnold, K. S., Taylor, S., Taylor, J. M., Innerarity, T. L. Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc. Nat. Acad. Sci. 92: 8483-8487, 1995. [PubMed: 7667315] [Full Text: https://doi.org/10.1073/pnas.92.18.8483]