Targeted Disruption of the Mouse apobec-1 Gene Abolishes Apolipoprotein B mRNA Editing and Eliminates Apolipoprotein B48

Hirano, Ken‐ichi; Young, Stephen G.; Farese, Robert V.; Ng, Jennifer K.; Sande, Eric; Warburton, Cara; Powell-Braxton, Lyn; Davidson, Nicholas O.

doi:10.1074/jbc.271.17.9887

Cited by 132 publications

(116 citation statements)

References 29 publications

(24 reference statements)

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“…As a positive control for this experiment, antisense oligonucleotide inhibition of apobec-1 expression demonstrated the anticipated elimination of editing activity (Fig. 9D, lanes 13-15), findings consistent with the results of gene targeting in mice (12,49,50). We have extended this paradigm with the demonstration that antisense oligonucleotide inhibition of ACF also results in loss of editing activity (Fig.…”

Section: Fig 6 Cugbp2 Is An Apob Rna-binding Proteinsupporting

confidence: 71%

Novel Role for RNA-binding Protein CUGBP2 in Mammalian RNA Editing

Anant¹,

Henderson²,

Mukhopadhyay³

et al. 2001

Journal of Biological Chemistry

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Mammalian apolipoprotein B (apoB) mRNA editing is mediated by a multicomponent holoenzyme containing apobec-1 and ACF. We have now identified CUGBP2, a 54-kDa RNA-binding protein, as a component of this holoenzyme. CUGBP2 and ACF co-fractionate in bovine liver S-100 extracts, and addition of recombinant apobec-1 leads to assembly of a holoenzyme. Immunodepletion of CUGBP2 co-precipitates ACF, and these proteins co-localize the nucleus of transfected cells, suggesting that CUGBP2 and ACF are bound in vivo. CUGBP2 binds apoB RNA, specifically an AU-rich sequence located immediately upstream of the edited cytidine. ApoB RNA from McA cells, bound to CUGBP2, was more extensively edited than the unbound fraction. However, addition of recombinant CUGBP2 to a reconstituted system demonstrated a dose-dependent inhibition of C to U RNA editing, which was rescued with either apobec-1 or ACF. Antisense CUGBP2 knockout increased endogenous apoB RNA editing, whereas antisense knockout of either apobec-1 or ACF expression eliminated apoB RNA editing, establishing the absolute requirement of these components of the core enzyme. These data suggest that CUGBP2 plays a role in apoB mRNA editing by forming a regulatory complex with the three components of the minimal editing enzyme, apobec-1, ACF, and apoB RNA.

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Section: Fig 6 Cugbp2 Is An Apob Rna-binding Proteinsupporting

confidence: 71%

Novel Role for RNA-binding Protein CUGBP2 in Mammalian RNA Editing

Anant¹,

Henderson²,

Mukhopadhyay³

et al. 2001

Journal of Biological Chemistry

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“…The effects depended completely on the direction of the cross (Table 3), with Apobec1 acting in the female germ-lineage, and Dnd1 acting in the male germ-lineages. Loss of substantial numbers of single and double heterozygotes in the interaction test is remarkable, given that both ko/ko and Ter/Ter homozygotes are fully viable in separate crosses (36,42). Normal segregation also is found in mutant heterozygotes in separate crosses to wild-type mice (29; also see Table S3), showing that gametes are produced in normal ratios and functionality.…”

Section: Discussionmentioning

confidence: 99%

“…Test 2: Parental ko/+ heterozygosity. Because partial Apobec1 deficiency can lead to tissue-specific dysfunction (42,47), we asked whether parental ko/+ heterozygosity affected TGCT susceptibility (cross 2). For this test, we measured the frequency of affected ko/+ (test) wild type and (+/+) w (control) male offspring from reciprocal crosses between ko/+ heterozygotes and strain 129 wild-type (+/+) c homozygotes.…”

Section: Resultsmentioning

confidence: 99%

“…Recent evidence suggests that several deaminases in the Apobec1 family also have DNA demethylase activity (39)(40)(41). Targeted deletion of Apobec1 (abbreviated ko hereafter) results both in homozygous mice that are healthy and fertile and in knockout heterozygotes that show tissue-specific abnormalities in ApoB RNA editing (42). The present study focused on tests to determine whether Apobec1 deficiency affects TGCT susceptibility in a conventional or transgenerational manner, either alone or in combination with Dnd1 Ter .…”

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confidence: 99%

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Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

Nelson

Heaney

Tesar

et al. 2012

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

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Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT-susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner.epigenetics | testicular cancer | gametogenesis | epistasis E stablishing the genetic basis and mode of inheritance for most traits and diseases has proven to be remarkably elusive (1). Susceptibility to testicular germ cell tumors (TGCTs) is illustrative (2). Testicular cancer is the most common malignancy affecting young men (3), more than 90% of testicular cancers result from TGCTs (4), TGCTs rank third in heritability among all cancers (5), and family history is the strongest known risk factor with a two-to sixfold increase among sons and a 5-to 19-fold increase among brothers of affected individuals (6-9). Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10-14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15-17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TG...

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“…It is known that not all genes tested by RNAi have visible phenotypes when inhibited [27], and a cdd knock-out gene might fall into this category. In the mouse, deletion of apobec-1 did not provide any gross phenotype, except for the absence of apoB48 in the serum [31]. Recent studies on mammalian CDDs have revealed the existence of a family of related proteins [6], and in the C. elegans genome there is at least one other predicted protein that could potentially compensate for any phenotype obtained by RNAi with Ce-cdd-1 and -2.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and molecular characterization of two cytidine deaminases in the nematode Caenorhabditis elegans

Thompson

Britton

Wheatley

et al. 2002

Biochemical Journal

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Two cytidine deaminases (CDDs) from the free-living nematode Caenorhabditis elegans have been cloned and characterized. Both Ce-CDD-1 and Ce-CDD-2 are authentic deaminases and both exhibit RNA-binding activity towards AU-rich templates. In order to study their temporal and spatial expression patterns in the worm, reporter gene constructs were made using approx. 2kb of upstream sequence. Transfection of C. elegans revealed that both genes localized to the cells of the intestine, although their temporal expression patterns were different. Expression of Ce-cdd-1 peaked in the early larval stages, whereas Ce-cdd-2 was expressed in all life cycle stages examined. RNA-interference (RNAi) assays were performed for both genes, either alone or in combination, but only cdd-2 RNAi produced a consistent visible phenotype. A proportion of eggs laid from these worms were swollen and distorted in shape.

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Targeted Disruption of the Mouse apobec-1 Gene Abolishes Apolipoprotein B mRNA Editing and Eliminates Apolipoprotein B48

Cited by 132 publications

References 29 publications

Novel Role for RNA-binding Protein CUGBP2 in Mammalian RNA Editing

Novel Role for RNA-binding Protein CUGBP2 in Mammalian RNA Editing

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

Biochemical and molecular characterization of two cytidine deaminases in the nematode Caenorhabditis elegans

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