C-to-U RNA Editing: Mechanisms Leading to Genetic Diversity (2003)

adenosine deaminases acting on double-stranded RNA apolipoprotein apobec-1 complementation factor neurofibromatosis type 1 activation-induced deaminase RNA editing is an important mechanism for regulating genetic plasticity through the generation of alternative protein products from a single structural gene. Substitutional RNA editing employs a variety of genetic mechanisms, the biochemical basis of which has been elucidated following the development of in vitroassays that recapitulate important elements of this process. Two types of substitutional RNA exist in mammals, namely A-to-I and C-to-U RNA editing (1Gott J.M. Emeson R.B. Annu. Rev. Genet. 2000; 34: 499-531Crossref PubMed Scopus (355) Google Scholar, 2Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). Important biochemical distinctions between these two processes provide an informative basis for understanding the mechanisms of C-to-U RNA editing and the adaptations that control target specificity. A-to-I RNA editing is mediated by a family of adenosine deaminases acting on double-stranded RNA (ADARs)1 with partially overlapping target specificity (1Gott J.M. Emeson R.B. Annu. Rev. Genet. 2000; 34: 499-531Crossref PubMed Scopus (355) Google Scholar, 2Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar). The absolute requirement for a double-stranded RNA template distinguishes A-to-I and C-to-U RNA editing because the former requires a pre-mRNA template containing intronic regions and is thus biochemically confined to unspliced transcripts. A further distinction biochemically is that ADAR enzymes do not require additional cofactors. ADARs contain both double-stranded RNA binding domains and a deaminase domain and function as modular editing enzymes (2Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 3Seeburg P.H. Neuron. 2002; 35: 17-20Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The best characterized example of C-to-U RNA editing involves the nuclear transcript encoding intestinal apolipoprotein B (apoB) (4Anant S. Davidson N.O. Curr. Opin. Lipidol. 2001; 12: 159-165Crossref PubMed Scopus (69) Google Scholar). ApoB RNA editing changes a CAA to aUAA stop codon, generating a truncated protein, apoB48 (4Anant S. Davidson N.O. Curr. Opin. Lipidol. 2001; 12: 159-165Crossref PubMed Scopus (69) Google Scholar). ApoB RNA editing has important effects on lipoprotein metabolism, and its emergence defines distinct pathways for intestinal and hepatic lipid transport in mammals (4Anant S. Davidson N.O. Curr. Opin. Lipidol. 2001; 12: 159-165Crossref PubMed Scopus (69) Google Scholar). C-to-U editing of apoB RNA requires a single-strand template (Fig. 1) with well defined characteristics in the immediate vicinity of the edited base, as well as protein cofactors that assemble into a functional complex referred to as a holoenzyme or editosome. This functional complex includes a minimal core composed of apobec-1, the catalytic deaminase, and a competence factor, apobec-1 complementation factor (ACF), that functions as an adaptor protein by binding both the deaminase and the RNA substrate (Fig. 1). The interaction of these protein components and their higher order interactions with the nuclear transcript illustrates the complexity of site-selectivity in C-to-U RNA editing. A second example of C-to-U RNA editing in mammals involves site-specific deamination of a CGA to UGA codon in the neurofibromatosis type 1 (NF1) mRNA (5Skuse G.R. Cappione A.J. Sowden M. Metheny L.J. Smith H.C. Nucleic Acids Res. 1996; 24: 478-485Crossref PubMed Scopus (80) Google Scholar). NF1 RNA editing generates a translational termination codon at position 3916 that is predicted to truncate the protein product neurofibromin at the 5′ end of a critical domain (6Cichowski K. Jacks T. Cell. 2001; 104: 593-604Abstract Full Text Full Text PDF PubMed Scopus (493) Google Scholar) involved in GTPase activation (Fig. 2). Unlike apoB RNA editing, there is no formal proof that a truncated protein is generated. This example of C-to-U RNA editing has been demonstrated in peripheral nerve sheath tumors from patients with NF1 and may share elements of the same machinery as apoB RNA editing, as discussed below. A third target for C-to-U editing, NAT1, was revealed following forced transgenic overexpression of apobec-1 in murine and rabbit hepatocytes (7Yamanaka S. Poksay K.S. Arnold K.S. Innerarity T.L. Genes Dev. 1997; 11: 321-333Crossref PubMed Scopus (188) Google Scholar). NAT1 is homologous to the translational repressor eIF4G and undergoes C-to-U editing at multiple sites, with the creation of stop codons that in turn reduce protein abundance (7Yamanaka S. Poksay K.S. Arnold K.S. Innerarity T.L. Genes Dev. 1997; 11: 321-333Crossref PubMed Scopus (188) Google Scholar). C-to-U RNA editing of endogenous apoB in vivo is largely confined to spliced and polyadenylated nuclear transcripts (8Lau P.P. Xiong W.J. Zhu H.J. Chen S.H. Chan L. J. Biol. Chem. 1991; 266: 20550-20554Abstract Full Text PDF PubMed Google Scholar). More recent studies using an apoB editing cassette cloned into constructs containing intronic sequences and transfected into cells that support C-to-U RNA editing suggest two important findings (9Sowden M.P. Smith H.C. Biochem. J. 2001; 359: 697-705Crossref PubMed Scopus (16) Google Scholar). First, introns suppress editing, an effect rescued by mutating the splice donor and acceptor sites in the chimeric cassette (9Sowden M.P. Smith H.C. Biochem. J. 2001; 359: 697-705Crossref PubMed Scopus (16) Google Scholar). Second, a Rev complementation assay used to produce conditional export of unspliced apoB RNA demonstrated that unspliced RNA is intrinsically capable of undergoing editing (9Sowden M.P. Smith H.C. Biochem. J. 2001; 359: 697-705Crossref PubMed Scopus (16) Google Scholar). These results, considered together with the earlier in vivo findings, suggest several testable conclusions. First, apoB RNA editing occurs in the nucleus and is selective for spliced transcripts rather than pre-mRNA. This is a crucial finding, because A-to-I RNA editing occurs beforesplicing. Second, spliceosome assembly itself or alternatively targeting RNA to the splicing pathway inhibits C-to-U editing. Plausible mechanisms for such inhibition include protein-protein or protein-RNA interactions between components of the spliceosome and the apoB RNA editing holoenzyme that hinder enzymatic activity in the latter. How might these possibilities be reconciled in the in vivo situation? In the context of mammalian apoB, splice donor and acceptor interactions at the termini of a large exon (exon 26, >7 kb) would likely be physically remote from the site of assembly and action of the editing enzyme. It is worth noting, however, that formation of a double-stranded template for A-to-I RNA editing requires base-pairing between the exonic region containing the targeted base and sequences within an adjacent intron, which in some instances are located ∼2 kb downstream (3Seeburg P.H. Neuron. 2002; 35: 17-20Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The availability of additional structural models for large transcripts should permit direct experimental validation of these possibilities. ApoB RNA editing is exquisitely site-specific, targeting a single cytidine in a transcript spanning greater than 14,000 residues. However, the minimal sequence information for this process appears contained within ∼30 nucleotides flanking the edited base (10Backus J.W. Smith H.C. Nucleic Acids Res. 1991; 19: 6781-6786Crossref PubMed Scopus (58) Google Scholar, 11Shah R.R. Knott T.J. Legros J.E. Navaratnam N. Greeve J.C. Scott J. J. Biol. Chem. 1991; 266: 16301-16304Abstract Full Text PDF PubMed Google Scholar), with more distant elements both 5′ and 3′ permitting enzymatic deamination with greater efficiency (12Hersberger M. Innerarity T.L. J. Biol. Chem. 1998; 273: 9435-9442Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 13Hersberger M. Patarroyo-White S. Arnold K.S. Innerarity T.L. J. Biol. Chem. 1999; 274: 34590-34597Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). An 11-nucleotide mooring sequence located 4–6 nucleotides downstream of the edited base is particularly important (10Backus J.W. Smith H.C. Nucleic Acids Res. 1991; 19: 6781-6786Crossref PubMed Scopus (58) Google Scholar, 11Shah R.R. Knott T.J. Legros J.E. Navaratnam N. Greeve J.C. Scott J. J. Biol. Chem. 1991; 266: 16301-16304Abstract Full Text PDF PubMed Google Scholar), but selection of the editing site likely also depends upon RNA secondary structure. RNase mapping and folding algorithms together predict that the apoB template folds into a stem-loop structure with the targeted cytidine located within an exposed loop of RNA (13Hersberger M. Patarroyo-White S. Arnold K.S. Innerarity T.L. J. Biol. Chem. 1999; 274: 34590-34597Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 14Richardson N. Navaratnam N. Scott J. J. Biol. Chem. 1998; 273: 31707-31717Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). A consensus binding site for apobec-1 (UUUN(A/U)U) was determined by circular permutation analysis and is predicted to be located 3 nucleotides downstream of the editing site, partially overlapping the 5′ terminus of the mooring sequence, at the apex of a stem-loop (Fig. 1) (15Anant S. Davidson N.O. Mol. Cell. Biol. 2000; 20: 1982-1992Crossref PubMed Scopus (82) Google Scholar). Identification of a consensus binding site for apobec-1 provides an additional screen for other RNAs that may be substrates for this enzyme. Among these candidate targets are RNA transcripts containing the consensus binding site embedded within the canonical destabilization element (UUAUU(A/U)(A/U)), which is found in the 3′-untranslated region of RNAs known to be regulated through alteration in stability (15Anant S. Davidson N.O. Mol. Cell. Biol. 2000; 20: 1982-1992Crossref PubMed Scopus (82) Google Scholar). A second candidate C-to-U editing template was identified through homology searches, which revealed that a CGA codon in the NF1 mRNA was changed to a UGA stop codon (5Skuse G.R. Cappione A.J. Sowden M. Metheny L.J. Smith H.C. Nucleic Acids Res. 1996; 24: 478-485Crossref PubMed Scopus (80) Google Scholar, 16Cappione A.J. French B.L. Skuse G.R. Am. J. Hum. Genet. 1997; 60: 305-312PubMed Google Scholar). Alignment of a 40-nucleotide NF1 mRNA encompassing the editing site reveals 50% identity with apoB mRNA, with 6 of 11 mismatches in the downstream cassette encoding the mooring sequence (Fig. 2). Recent studies have demonstrated several important features concerning C-to-U RNA editing of NF1 in tumors from these patients. First, the subset of tumors that demonstrate C-to-U RNA editing of NF1 contain high levels of an alternatively spliced downstream exon (exon 23A, Fig. 2) (17Mukhopadhyay D. Anant S. Lee R.M. Kennedy S. Viskochil D. Davidson N.O. Am. J. Hum. Genet. 2002; 70: 38-50Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). RNA modeling predictions suggest that inclusion of the 63-nucleotide exon resulting from alternative splicing permits the transcript to fold into a more favorable configuration with respect to access of the active site of the deaminase to the targeted cytidine. 2D. Mukhopadhyay and N. O. Davidson, unpublished observations. Second, tumors that demonstrate C-to-U RNA editing express apobec-1 mRNA, the transcript encoding the catalytic deaminase of the apoB RNA editing holoenzyme. In addition, a consensus apobec-1 binding site has been identified upstream of the editing site and appears functional as evidenced by UV-cross-linking studies (17Mukhopadhyay D. Anant S. Lee R.M. Kennedy S. Viskochil D. Davidson N.O. Am. J. Hum. Genet. 2002; 70: 38-50Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar). Taken together, the findings suggest that C-to-U RNA editing of NF1 may share certain elements of the apoB RNA editing machinery, although editing occurs at lower efficiency (<20% for NF1 versus >90% for intestinal apoB), presumably the result of mooring sequence mismatches. ApoB RNA editing is mediated by a multicomponent complex with a minimal, two-component core composed of the catalytic deaminase apobec-1 (4Anant S. Davidson N.O. Curr. Opin. Lipidol. 2001; 12: 159-165Crossref PubMed Scopus (69) Google Scholar) and a competence factor, ACF (18Mehta A. Kinter M.T. Sherman N.E. Driscoll D.M. Mol. Cell. Biol. 2000; 20: 1846-1854Crossref PubMed Scopus (221) Google Scholar, 19Lellek H. Kirsten R. Diehl I. Apostel F. Buck F. Greeve J. J. Biol. Chem. 2000; 275: 19848-19856Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Apobec-1 is highly conserved and likely evolved from a common ancestral cytidine deaminase (20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar). Like most cytidine deaminases, apobec-1 functions as a dimer (20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar), with a composite active site representing asymmetric contributions from each monomer that permits both substrate binding and deamination, together with a leucine-rich pseudoactive site at the carboxyl terminus, involved in dimerization (20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar). The active site residues and their spacing are conserved in all cytidine deaminases and define a signature motif (HXE(X)nPCXXC) for this gene family. Apobec-1, unlike the Escherichia coli homolog, demonstrates RNA binding activity, which requires two aromatic residues (Phe-66, Phe-87) within the catalytic site (20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar). Apobec-1 has no canonical RNA binding motifs in its primary sequence. However, mutations that interfere with RNA binding do not function in C-to-U RNA editing despite retaining cytidine deaminase activity (15Anant S. Davidson N.O. Mol. Cell. Biol. 2000; 20: 1982-1992Crossref PubMed Scopus (82) Google Scholar, 20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar). Accordingly, apobec-1 is proposed to have evolved from an ancient cytidine deaminase that has acquired RNA specificity, allowing targeted nucleoside deamination of an RNA (20Navaratnam N. Fujino T. Bayliss J. Jarmuz A. How A. Richardson N. Somasekaram A. Bhattacharya S. Carter C. Scott J. J. Mol. Biol. 1998; 275: 695-714Crossref PubMed Scopus (126) Google Scholar). As alluded to above, forced transgenic overexpression of apobec-1 led to a cancer phenotype in the setting of promiscuous editing of cytidines in both apoB RNA and NAT1, a translational inhibitor involved in early embryogenesis (7Yamanaka S. Poksay K.S. Arnold K.S. Innerarity T.L. Genes Dev. 1997; 11: 321-333Crossref PubMed Scopus (188) Google Scholar, 21Yamanaka S. Zhang X.Y. Maeda M. Miura K. Wang S. Farese R.V., Jr. Iwao H. Innerarity T.L. EMBO J. 2000; 19: 5533-5541Crossref PubMed Scopus (74) Google Scholar). This gain of function phenotype implies that overexpression of apobec-1 is deleterious to the organism, although the proximate mechanism leading to dysplasia and cancer is yet to be defined. Consistent with this implication, host adaptations modulate the expression of apobec-1 in sporadic human colorectal cancer and in experimental colonic adenoma-carcinoma formation in carcinogen-treated rats (22Lee R.M. Hirano K. Anant S. Baunoch D. Davidson N.O. Gastroenterology. 1998; 115: 1096-1103Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 23Greeve J. Lellek H. Apostel F. Hundoegger K. Barialai A. Kirsten R. Welker S. Greten H. Oncogene. 1999; 18: 6357-6366Crossref PubMed Scopus (20) Google Scholar, 24Anant S. Mukhopadhyay D. Hirano K. Brasitus T.A. Davidson N.O. Biochim. Biophys. Acta. 2002; 1575: 54-62Crossref PubMed Scopus (12) Google Scholar). EST data base searches for apobec-1-related proteins based on the signature motif has revealed new members of the gene family. Among these, apobec-2/ARCD1 is located on chromosome 6 and represents an abundant transcript in heart and skeletal muscle (25Liao W. Hong S.H. Chan B.H. Rudolph F.B. Clark S.C. Chan L. Biochem. Biophys. Res. Commun. 1999; 260: 398-404Crossref PubMed Scopus (113) Google Scholar, 26Anant S. Mukhopadhyay D. Sankaranand V. Kennedy S. Henderson J.O. Davidson N.O. Am. J. Physiol. 2001; 281: C1904-C1916Crossref PubMed Google Scholar). Apobec-2/ARCD1 is an authentic cytidine deaminase with apoB RNA binding activity but does not mediate C-to-U editing of apoB RNA, and its primary target, if any, is unknown (26Anant S. Mukhopadhyay D. Sankaranand V. Kennedy S. Henderson J.O. Davidson N.O. Am. J. Physiol. 2001; 281: C1904-C1916Crossref PubMed Google Scholar). However, ARCD1 interacts physically with both apobec-1 and ACF and inhibits apoB RNA editing in trans, possibly through interactions that alter the or of the holoenzyme (26Anant S. Mukhopadhyay D. Sankaranand V. Kennedy S. Henderson J.O. Davidson N.O. Am. J. Physiol. 2001; 281: C1904-C1916Crossref PubMed Google Scholar). This is with the inhibition of A-to-I RNA editing of by a third of the ADAR family Wang F. Carter K. 2000; PubMed Scopus Google Scholar). apobec-1 homolog, activation-induced deaminase is in B and is for The for human is adjacent to that on that may a gene (26Anant S. Mukhopadhyay D. Sankaranand V. Kennedy S. Henderson J.O. Davidson N.O. Am. J. Physiol. 2001; 281: C1904-C1916Crossref PubMed Google Scholar, A. A. Bayliss J. J. I. Scott J. Navaratnam N. 2002; PubMed Scopus Google Scholar). of a murine of resulting from a in M. K. S. S. T. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and mutations in the human demonstrated in the of T. F. A. O. N. M. R. A. I. F. H. N. M. K. T. A. A. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is to apobec-1 and demonstrates cytidine deaminase activity yet does not demonstrate RNA binding or RNA editing activity on of the known substrates (26Anant S. Mukhopadhyay D. Sankaranand V. Kennedy S. Henderson J.O. Davidson N.O. Am. J. Physiol. 2001; 281: C1904-C1916Crossref PubMed Google Scholar, M. K. S. S. T. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the that its primary target may be and not RNA 2002; PubMed Scopus Google Scholar). An additional of has been found on chromosome all structural features of the cytidine deaminase active site above, the aromatic residues critical for RNA binding activity, and demonstrates RNA binding activity for of these gene products demonstrate C-to-U editing activity on known RNA template A. A. Bayliss J. J. I. Scott J. Navaratnam N. 2002; PubMed Scopus Google Scholar). of encoding these particularly and appears and several are found at abundance in and cancer the that may be involved in or A. A. Bayliss J. J. I. Scott J. Navaratnam N. 2002; PubMed Scopus Google Scholar). of revealed that C-to-U RNA editing activity as a I. J.W. Smith H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar) leading to the of a multicomponent editing to complementation on the that these would apoB mRNA This was but and the recent of ACF by two represents a in the (18Mehta A. Kinter M.T. Sherman N.E. Driscoll D.M. Mol. Cell. Biol. 2000; 20: 1846-1854Crossref PubMed Scopus (221) Google Scholar, 19Lellek H. Kirsten R. Diehl I. Apostel F. Buck F. Greeve J. J. Biol. Chem. 2000; 275: 19848-19856Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). ACF together with apobec-1 is to mediate C-to-U editing of apoB RNA (18Mehta A. Kinter M.T. Sherman N.E. Driscoll D.M. Mol. Cell. Biol. 2000; 20: 1846-1854Crossref PubMed Scopus (221) Google Scholar, 19Lellek H. Kirsten R. Diehl I. Apostel F. Buck F. Greeve J. J. Biol. Chem. 2000; 275: 19848-19856Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar), and these two in or in the minimal core of the holoenzyme H. Welker S. Diehl I. Kirsten R. Greeve J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). ACF is a protein, in human (18Mehta A. Kinter M.T. Sherman N.E. Driscoll D.M. Mol. Cell. Biol. 2000; 20: 1846-1854Crossref PubMed Scopus (221) Google Scholar, 19Lellek H. Kirsten R. Diehl I. Apostel F. Buck F. Greeve J. J. Biol. Chem. 2000; 275: 19848-19856Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Alignment of the predicted structural motifs within ACF reveals the of RNA motifs at the terminus, with a double-stranded RNA binding domain and 6 within the carboxyl terminus (18Mehta A. Kinter M.T. Sherman N.E. Driscoll D.M. Mol. Cell. Biol. 2000; 20: 1846-1854Crossref PubMed Scopus (221) Google Scholar, 19Lellek H. Kirsten R. Diehl I. Apostel F. Buck F. Greeve J. J. Biol. Chem. 2000; 275: 19848-19856Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). identified an ACF binding site in apoB RNA spanning a sequence the editing site and partially overlapping the end of the mooring sequence (Fig. 1) V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar). of ACF has identified the functional domains involved in apoB RNA apobec-1 and apobec-1 complementation of C-to-U editing. the apobec-1 interaction and apoB RNA binding domains are for C-to-U editing V. Henderson J.O. Kennedy S. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (46) Google Scholar, A. Driscoll D.M. 2002; PubMed Scopus (54) Google Scholar). However, the other RNA binding domains in ACF are the of these domains may other in RNA The human ACF kb on chromosome and distinct splice from J.O. V. Davidson N.O. Biochim. Biophys. Acta. 2001; PubMed Scopus Google Scholar). The of splice in human and reveals two ACF and the containing an as a result of alternative splicing of exon is no functional distinction between and V. Henderson J.O. Kennedy S. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (46) Google Scholar, Sowden M.P. L. Smith H.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). splice have been demonstrated at lower abundance in human and demonstrate or no of these splice J.O. V. Davidson N.O. Biochim. Biophys. Acta. 2001; PubMed Scopus Google Scholar). these a in to apoB RNA editing or other of RNA and function is Identification of other components of the holoenzyme Among these candidate components are two apoB RNA editing and V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar, S. Henderson J.O. Mukhopadhyay D. Navaratnam N. Kennedy S. J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (80) Google Scholar, P.P. B.H. Chan L. Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar). is a protein that with ACF and apoB RNA upstream of the editing site but inhibits apoB RNA editing in S. Henderson J.O. Mukhopadhyay D. Navaratnam N. Kennedy S. J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (80) Google Scholar). by is homologous to ACF V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar, P.P. B.H. Chan L. Biochem. Biophys. Res. Commun. 2001; PubMed Scopus Google Scholar) and functional characteristics the to apobec-1 as well as apoB RNA V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar). In addition, in the nucleus with ACF and with apobec-1 but does not apobec-1 in C-to-U RNA editing. inhibits editing in and in vivo in a by ACF or alternatively apobec-1 apoB RNA V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar). This of interactions the of a of targets for these several of the candidate proteins proposed for the apoB RNA holoenzyme and identified through their to apoB RNA through their interaction with apobec-1 have been demonstrated to in other RNA mRNA and has been identified as a of the nuclear family L. J. N. EMBO J. 2001; 20: PubMed Scopus Google Scholar). Two using apobec-1 as revealed interactions with several Among these, nuclear inhibits apoB RNA editing in J. Lellek H. Greten H. Biol. Chem. 1998; PubMed Scopus Google Scholar). Two other and are homologous to human nuclear and P.P. H. K. M. B.H. Chan L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P.P. Zhu H.J. M. Chan L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). direct for a primary for protein in apoB RNA editing in although of protein in apoB RNA editing from from cells P.P. H. K. M. B.H. Chan L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P.P. Zhu H.J. M. Chan L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The of these proteins in apoB RNA editing further of endogenous apobec-1 has because this is a abundance protein but the data from studies a V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar, Sowden M.P. Smith H.C. 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Chem. 2001; Full Text Full Text PDF PubMed Scopus (46) Google Scholar). of apobec-1 with ACF to within the nucleus of transfected cells V. Navaratnam N. Henderson J.O. Anant S. Kennedy S. Jarmuz A. Scott J. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (82) Google Scholar, V. Henderson J.O. Kennedy S. Davidson N.O. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus (46) Google Scholar), and of nuclear the of ACF within large demonstrated to contain editing activity M.P. N. Smith H.C. J. Sci. 2002; 115: PubMed Google Scholar). These findings suggest that interaction of apobec-1 with ACF their into the nucleus and formation of a holoenzyme of the mechanisms regulating the of the core components of the apoB RNA editing holoenzyme be of Recent findings suggest that nuclear of apobec-1 and ACF may a mechanism for the of C-to-U editing activity, presumably by the and of the components to the site of of the substrate M.P. N. Smith H.C. J. Sci. 2002; 115: PubMed Google Scholar). involves an mechanism to that for the nuclear of the factor or the type protein W. M. J. Biol. PubMed Scopus Google H. Cell. Full Text PDF PubMed Scopus Google Scholar). This is with the of nuclear abundance of ACF following or M.P. N. Smith H.C. J. Sci. 2002; 115: PubMed Google Scholar). C-to-U RNA editing is an important mechanism for mammalian genetic in a regulated to the of this is the to define and access of the machinery to enzymatic within The of the core components of the apoB RNA editing holoenzyme and the to the of new candidate that elements of the complex likely further functions in RNA functional between these distinct should an for