Antisense globin RNA in mouse erythroid tissues: structure, origin, and possible function.

Volloch, Vladimir; Schweitzer, Bruce; Rits, Sophia

doi:10.1073/pnas.93.6.2476

Cited by 48 publications

(157 citation statements)

References 25 publications

(41 reference statements)

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“…There is, however, another possibility of utilization of the A UG1786 as a translation initiation codon, namely the generation of a 5'-truncated pAPP mRNA in which the A UG1786 becomes thefirst AUG codon. A possible mechanism for the generation of such a truncated pAPP mRNA is suggested by recent results from the author's laboratory with globin mRNA in erythroid precursor cells [25].…”

Section: The Modelmentioning

confidence: 99%

“…Elucidation of the structure of antisense globin RNA suggested a possible mechanism [25] thesis of antisense RNA is initiated within the poly(A) region of mRNA, presumably by a mechanism similar to that employed in viral systems [26]; consequently, it contains a poly(U) stretch at the 5' end. At the 3' end, antisense RNA contains two strongly complementary elements within the segment corresponding to the 5'-untranslated region of globin mRNA.…”

Section: The Modelmentioning

confidence: 99%

“…A possible solution to this potential problem is to , nalyze a sufficient number of samples from 'normal' subjects, , ld enough to have relatively high probability of developing xD. Secondly, by analogy with globin mRNA replication in Lrythroid precursor cells ( [25]; V. Volloch, unpublished results), 5'-truncated ~APP mRNA encoding the 12-kDa lAPP fragment may be heavily modified and consequently hybridize poorly with specific probes at high stringency conditions. Therefore, an initial search for ~APP antisense RNA appears to be the most efficient way to pursue this proposal.…”

Section: Predictions and Conclusionmentioning

confidence: 99%

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A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

Volloch

1996

FEBS Letters

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The overproduction of ~amyloid (A~) appears to be a primary cause of Alzheimer's disease (AD). Ap can be generated by proteolytic cleavage of precursor protein (pAPP) at I~ and 7-secretasc sites in both disease and normal cells. There is, however, no evidence that proteolytic processing of ~APP in sporadic AD-affected tissues differs qualitatively or quantitatively from that occurring in normal cells, and additional pathways for the enhanced production of A~ in sporadic AD which constitutes the majority of all AD cases should be considered. The major factor limiting the production of A~ in normal cells is cleavage at the ~t-secretase site within the A~ sequence. But, whereas the intact ~APP is a substrate for cleavage at the ~secretase site, the immediate precursor of Ap, 12-kDa C-terminal ~APP fragment, is not susceptible to the ot-secretase cleavage but it can be cleaved by ~secretase thus generating A~. Moreover, the 7-secretase cleavage is not the ratelimiting step in the production of A~. Therefore, the increase in production of the 12-kDa C-terminal ~APP fragment may be an efficient way to overproduce A~. A mechanism for the generation of the 12-kDa fragment independently of pAPP is proposed. It postulates an additional step of amplification of mRNA, namely the antisense RNA-mediated generation of a truncated mRNA encoding 12-kDa C-terminal fragment. Initiation of translation at the first AUG in the truncated mRNA results in a polypeptide that is cleaved by ~'-secretase generating Ap. The proposed model makes several verifiable predictions and suggests new directions of experimentation that may lead to a better understanding of the mechanisms involved in AD.Key words: Alzheimer's disease; ~-Amyloid precursor protein (pAPP); [~-Amyloid (AI~); [~-Amyloid overproduction; Antisense RNA; mRNA replication cells from patients with a defect in the S182 gene, associated with the most common form of the early-onset AD, make abnormally high amounts of Ap [5]; Down syndrome, associated with trisomy 21 and, consequently, increased dosage of the 13APP gene which is located on chromosome 21, is characterized by increased levels of pAPP gene expression and by the early cerebral deposition of AI~ [6,7]. The most convincing evidence for the notion that overproduction of Ap is sufficient to trigger AD comes from experiments with transgenic mice overexpressing full-length human pAPP, which generate high levels of AI~ and develop AD-like neuropathology [8].AI~ can be produced by proteolysis of pAPP, a process that occurs constitutively in both normal and AD-affected tissues as well as in cultured cells [8][9][10][11][12], and its overproduction in AD is currently explained in terms of proteolytic processing of I~APP. pAPP proteolysis is effected by yet to be identified enzymes designated t~-, [~-and y-secretases ( Fig. 1) and occurs at Met596/Asp 597 (13-secretase; pAPP695 numbering), at Lys612/Leu 613 (ct-secretase) and between Va1635 and Thr 639 (y-secretase). Cleavage by 13-secretase generates an ectodomain fragmen...

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Section: The Modelmentioning

confidence: 99%

Section: The Modelmentioning

confidence: 99%

Section: Predictions and Conclusionmentioning

confidence: 99%

See 1 more Smart Citation

A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

Volloch

1996

FEBS Letters

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“…Regardless, the ability of cells to replicate an exogenous HDV RNA without an exogenous polymerase implies that mammalian cells have an innate capacity to replicate other exogenous RNA or their own cellular RNA. RNA-dependent RNA synthesis in certain mammalian cells has been documented on several occasions (68). Recent small interfering RNA studies further suggest that certain RNA species may be amplified by RNA-dependent RNA replication in the cells.…”

Section: Perspectivesmentioning

confidence: 99%

RNA Replication without RNA-Dependent RNA Polymerase: Surprises from Hepatitis Delta Virus

Lai

2005

J Virol

130

119

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RNA-dependent RNA replication is a special process reserved exclusively for RNA viruses but not cellular RNAs. Almost all RNA viruses (except retroviruses) undergo RNAdependent RNA replication by a virus-encoded RNA-dependent RNA polymerase (RdRP), which specifically replicates the viral RNA genome. Satellite viral RNAs do not encode their own polymerase but rely on the RdRP from the coexisting helper virus for their replication. Hepatitis delta virus (HDV) and plant viroids present an exception which still confounds the conventional thinking. None of them encode an RdRP, and yet they can undergo robust RNA replication autonomously once inside the cells. It is intuitive that they have to replicate their RNA genome using a cellular enzyme. However, unlike plants and lower animal species, which encode RdRPs that are putatively involved in gene silencing (11,13,57,58), no mammalian cells have been shown to encode any RdRP or its equivalent. Nevertheless, the RNA interference phenomena suggest the possibility that RNA-templated RNA amplification may also take place in the mammalian cells (61). Thus, viroids and HDV present both a challenge and an opportunity for understanding a potentially physiological flow of genetic information from RNA to RNA in the mammalian cells. Viroids and HDV differ in that viroids do not encode any protein, whereas HDV encodes a protein (hepatitis delta antigen [HDAg]) which is intimately involved in RNA replication. In addition, HDV RNA not only has to replicate itself but also needs to transcribe a subgenomic mRNA species that encodes HDAg. The transcription of the HDAg-encoding mRNA has all of the hallmarks of the conventional mRNA transcription in the cells except for the nature of the template (DNA versus RNA). Therefore, HDV represents a hybrid of the conventional DNA-dependent transcription and the unique RNAdependent RNA synthesis in the absence of an RdRP.HDV causes chronic, and occasionally fulminant, hepatitis (20). It is always associated with hepatitis B virus (HBV) infection because HDV cannot form virus particles on its own (54). It was prevalent worldwide, with a particularly high prevalence rate in the Mediterranean countries. In recent years, the incidence of new HDV infection has precipitously declined, partially due to HBV vaccination. Nevertheless, the scientific mystery surrounding HDV replication thickens. STRUCTURE OF HDV RNA AND HDAgHDV contains a circular RNA genome of 1.7 kilobases which can replicate on its own but requires HBV as the helper virus to supply HBV surface antigen for the production of virus particles. The genome sequence is nearly self-complementary such that the viral RNA forms a rodlike double-stranded RNA structure under the native conditions (29, 70). As such, HDV RNA is very similar to viroid RNAs; indeed, part of the HDV RNA sequence is evolutionarily related to viroids (15). However, HDV RNA is 3 to 4 times longer than the typical viroid, with the additional sequences being attributed to a coding sequence for HDAg on the complementary (anti...

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“…In other examples such as Drosophila melanogaster, cuticle protein (Henikoff et al 1986) and decarboxylase (Spencer et al 1986) genes, mouse tissue culture antisense transcripts (Williams & Fried 1986), cytochrome oxidase subunit III of Trypanosoma brucei (Volloch et al 1991), the mouse globin gene (Volloch et al 1996) and insulin-like growth factor-II (Sussenbach 1989), the role of antisense RNA transcription is unknown. Figure 4 Northern blots of mRNA from human tissues.…”

Section: Significance Of the Antisense Transcriptmentioning

confidence: 99%

A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

Millar

Conklin²,

Lofton–Day³

et al. 1999

Journal of Endocrinology

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Gonadotropin releasing hormone (GnRH) regulates the reproductive system through a specific G-protein-coupled receptor (GPCR) in pituitary gonadotropes. The existence of two (or more) forms of GnRH in most vertebrates suggested the existence of GnRH receptor subtypes (I and II). Using sequence information for extracellular loop 3 of a putative Type II GnRH receptor from a reptile species, we have looked for a Type II GnRH receptor gene in the human genome EST (expressed sequence tag) database. A homolog was identified which has 45% and 41% amino acid identity with exons 2 and 3 of the known human GnRH pituitary receptor (designated Type I) and much lower homology with all other GPCRs. A total of 27 contiguous ESTs was found and comprised a continuous sequence of 1642 nucleotides. The EST sequences were confirmed in the cloned human gene and in PCR products of cDNA from several tissues. All EST transcripts detected were in the antisense orientation with respect to the novel GnRH receptor sequence and were highly expressed in a wide range of human brain and peripheral tissues. PCR of cDNA from a wide range of tissues revealed that intronic sequence equivalent to intron 2 of the Type I GnRH receptor was retained. The failure to splice out putative intron sequences in transcripts which spanned exon-intron boundaries is expected in antisense transcripts, as candidate donor and acceptor sites were only present in the gene when transcribed in the orientation encoding the GnRH receptor homolog. No transcripts extended 5 to the sequence corresponding to intron 2 of the Type I GnRH as the antisense transcripts terminated in poly A due to the presence of a polyadenylation signal sequence in the putative intron 2 when transcribed in the antisense orientation. These findings suggest that a Type II GnRH receptor gene has arisen during vertebrate evolution and is also present in the human. However, the receptor may have become vestigial in the human, possibly due to the abundant and universal tissue transcription of the opposite DNA strand to produce antisense RNA.

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Antisense globin RNA in mouse erythroid tissues: structure, origin, and possible function.

Cited by 48 publications

References 25 publications

A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

RNA Replication without RNA-Dependent RNA Polymerase: Surprises from Hepatitis Delta Virus

A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

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