Hemoglobin Saverne: A New Variant with Elongated β Chains: Structural and Functional Properties

Delanoe-Garin, J.; Blouquit, Y.; Arous, N.; Kister, J.; Poyart, Claire; North, M. L.; Bardakdjian, J.; Lacombe, C.; Rosa, J.; Galactéros, Frédéric

doi:10.3109/03630268808998034

Cited by 26 publications

(9 citation statements)

References 27 publications

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“…The mutation causes the frame-shift reading of the β C-terminal code, leading to a new sequence of 13 additional residues: 144Ser-145Ileu-146Thr-147Lys-148Leu-149Ala-150Phe-151Leu-152Leu-153Ser-154Asn-155Phe-156Tyr. These are identical to those of Hb Saverne [8], originating from a different frame-shift mutation, but the stop signal TAA is shifted at codon 157 in both cases. Also Hb Tak and Cranston [9, 10]have elongated β C-terminal chains, and their frame-shift mutations are similar, but not identical, to those of Hb Saverne and Tr.…”

Section: Introductionsupporting

confidence: 51%

Functional Studies on Nine Different Haemoglobins with High Oxygen Affinity

David

Ivaldi²,

Rabino-Massa³

et al. 2002

Acta Haematol

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Nine carriers of β-abnormal haemoglobins with increased oxygen affinity (Hb X) were examined. Their oxygen dissociation curves from whole blood were more or less left-shifted, with six of nine also characterized by biphasism. This refers to an ‘inflection point’ usually positioned at about 50–60% of Hb O₂ saturation, commonly believed to be a limit between oxygenation of the normal and abnormal components. In effect, the inflection does not always correspond to the Hb X level, which sometimes is much lower than 50% of the total Hb. Moreover, the upper half segment of the dissociation curve could not only be an expression of Hb A oxygenation, since it is always left-shifted. However, a high Hb A level is commonly believed to be the main compensatory factor of these subjects, but many indications suggest that often they have at least three, and not only two, main haemoglobin species: Hb A, Hb X plus hybrids of the type α₂β^Aβ^X. These would oxygenate after Hb X, but before Hb A. Finally, the interaction of 2,3-diphosphoglycerate with Hb X and/or hybrid tetramers must be altered, and the releasing of oxygen from both is more or less reduced. Unfortunately, it is difficult to demonstrate the presence of hybrids directly, i.e. with amino acid analysis of the abnormal β-globin.

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Section: Introductionsupporting

confidence: 51%

Functional Studies on Nine Different Haemoglobins with High Oxygen Affinity

David

Ivaldi²,

Rabino-Massa³

et al. 2002

Acta Haematol

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“…Although ␤-globin genes have been described that contain single-nucleotide substitutions or small deletions within their 3Ј UTRs, these mutations do not appear to affect globin mRNA stability (2, 10, 29; data not shown). ␤-Globin genes containing frameshift antitermination mutations (permitting ribosomes to read through the initial third of the 3Ј UTR) are expressed at near-normal levels (9,18,19), suggesting that mRNA stability-defining determinants are positioned further downstream. ␤-Globin mRNAs containing engineered mutations that permit ribosomes to read further into the 3Ј UTR are destabilized both in cultured MEL cells (54), as well as in situ in whole-animal models ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…␤-Globin genes containing antitermination frameshift mutations permitting ribosomes to read through ␤ PRE-1 to a UAA termination codon 10 codons into the 3Ј UTR are expressed at normal or near-normal levels (9,18,19,54), suggesting that the structural integrity of ␤ PRE-1 is not required for high ␤-globin mRNA stability. Likewise, ␤ PRE-3 is a less attractive candidate than ␤ PRE-2 as a stabilizing cis element because of its short length (10 nt), cytosine deficiency (a single residue), and positioning 3Ј to the AAUAAA polyadenylation hexanucleotide.…”

Section: Vol 21 2001mentioning

confidence: 99%

“…Single-nucleotide conversions affecting pre-mRNA splicing or resulting in premature translational termination can accelerate ␤-globin mRNA degradation, but through pathways that are unlikely to affect a specific mRNA-stabilizing element (reviewed in references 8, 20, and 43). Likewise, frameshift mutations in the terminal coding region that permit ribosomes to read through the proximal one-third of the ␤ 3Ј UTR have relatively little impact on overall ␤-globin expression (9,18,19,54), suggesting that crucial stability elements are downstream of this region. It has also been suggested that ␤-globin mRNA stability might result from spatially distinct but functionally redundant cis elements (54).…”

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confidence: 99%

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Structural and Functional Analysis of an mRNP Complex That Mediates the High Stability of Human β-Globin mRNA

Jiao¹,

Russell

2001

Molecular and Cellular Biology

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Human globins are encoded by mRNAs exhibiting high stabilities in transcriptionally silenced erythrocyte progenitors. Unlike ␣-globin mRNA, whose stability is enhanced by assembly of a specific messenger RNP (mRNP) ␣ complex on its 3 untranslated region (UTR), neither the structure(s) nor the mechanism(s) that effects the high-level stability of human ␤-globin mRNA has been identified. The present work describes an mRNP complex assembling on the 3 UTR of the ␤-globin mRNA that exhibits many of the properties of the stability-enhancing ␣ complex. The ␤-globin mRNP complex is shown to contain one or more factors homologous to ␣CP, a 39-kDa RNA-binding protein that is integral to ␣-complex assembly. Sequence analysis implicates a specific 14-nucleotide pyrimidine-rich track within its 3 UTR as the site of ␤-globin mRNP assembly. The importance of this track to mRNA stability is subsequently verified in vivo using mice expressing human ␤-globin transgenes that contain informative mutations in this region. In combination, the in vitro and in vivo analyses indicate that the high stabilities of the ␣-and ␤-globin mRNAs are maintained through related mRNP complexes that may share a common regulatory pathway.Eukaryotic mRNAs display half-lives (t 1/2 s) that range from as short as several minutes (74) to as long as several days (1, 52). Although short-lived mRNAs are typically present in low abundance, their steady-state levels rapidly adjust to reflect fluctuations in gene transcriptional activity. In contrast, longlived mRNAs may accumulate to high levels that are relatively slow in responding to changes in gene transcription. It is not surprising that mRNAs encoding cytokines, proto-oncogenes, and factors that regulate gene transcription, cell growth, and cell cycling are generally short-lived (6, 49), while mRNAs encoding structural proteins (e.g., collagens) (24, 41) or highly abundant functional products (e.g., crystallins and globins) (4, 36, 52, 66) display longer t 1/2 s. Although the stabilities of most mRNAs are likely to be constitutive, some-including mRNAs encoding the transferrin receptor (34), histones (5), tubulin (15), and interleukin-2 (11, 12)-display dynamic stabilities that vary in response to changing cellular requirements or environmental conditions (reviewed in reference 49).The t 1/2 s of individual mRNAs reflect the combined effects of general and specific determinants of mRNA stability. Two nearly invariant features of eukaryotic mRNAs-the m 7 G(5Ј)ppp(5Ј)N cap (21, 60) and 3Ј poly(A) tail (7, 37, 73)-are believed to provide a basal level of stability to all mRNAs by preventing their degradation by cytoplasmic exonucleases. The mRNA-stabilizing properties of the poly(A) tail have been linked both to its poly(A)-binding protein-binding function (7, 50) and to its capacity to stimulate active translation (46; reviewed in references 49 and 57). In addition to these general determinants, a number of well-defined cis elements appear to mediate the stabilities of specific mRNAs. These structurally d...

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“…The latter studies were particularly informative, demonstrating that ␤-globin mRNA can be destabilized by engineered mutations that permit ribosomes to read past its native translational terminal codon and through the entire 3ЈUTR, disrupting hypothetical mRNP structures positioned in that region. In contrast, ␤-globin expression is minimally impacted by naturally occurring and synthetic frameshift mutations that restrict ribosomal readthrough to the proximal one-third of the 3ЈUTR (11,20,25,65), suggesting that critical determinants of mRNA stability are likely to be positioned further downstream. Scattered, naturally occurring single-nucleotide substitutions and small deletions in the terminal portion of the 3ЈUTR do not materially affect ␤-globin mRNA stability (3,12,34) and are consequently of little help in mapping important cis-acting stability elements.…”

mentioning

confidence: 99%

A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo

Jiang¹,

Xu²,

Russell

2006

Molecular and Cellular Biology

107

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The normal expression of human ␤ globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with ␣-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing ␤-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the ␤-globin 3 untranslated region (3UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by ␣CP/hnRNP-E, a factor that plays a critical role in stabilizing human ␣-globin mRNA. Mutations within the new determinant destabilize ␤-globin mRNA in intact cells while also ablating its 3UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3UTR-bound nucleolin enhances mRNA stability by optimizing ␣CP access to its functional binding site. This model is favored by in vitro evidence that ␣CP binding is enhanced both by cis-acting stem-destabilizing mutations and by the trans-acting effects of supplemental nucleolin. These studies suggest a mechanism for ␤-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human ␣-globin mRNA.Erythroid cells accumulate hemoglobin through a process that is critically dependent upon the high stabilities of mRNAs that encode their constituent ␣-and ␤-globin subunits (10, 64). In vivo analyses estimate a half-life for human ␣-globin mRNA of between 24 and 60 h (47,62,63,74), while similar studies with cultured NIH 3T3 and murine erythroleukemia (MEL) cells (2, 36, 42), primary mouse hematopoietic cells (4), and human erythroid progenitors (62, 63) suggest a half-life value for human ␤-globin mRNA that exceeds 16 to 20 h. Globin mRNAs survive, and continue to translate at high levels, for as long as a week following nuclear condensation and extrusion in transcriptionally silent erythroid progenitor cells. As might be anticipated, mutations that impair the normal stabilities of globin mRNAs can severely impact the levels of their encoded proteins. For example, an mRNA-destabilizing mutation reduces the expression of ␣ Constant Spring to less than 2% of normal levels (45,51,80), resulting in a clinically important form of thalassemia characterized by a substantial imbalance in ␣-and ␤-globin chain accumulation (10, 64).The cis-acting determinants and trans-acting factors that participate in regulating ␣-globin mRNA stability have recently been identified, and the relevant molecular mechanisms have been described in detail. Mutational analyses carried out with cultured cells (80, 81) and with animal models (52, 66) clearly demonstrate the importance of the 3Ј untranslated region (3ЈUTR) to the constitutively high stability of ␣-globin mRNA (45). Other studies have mapped this characteristic to a phylogenically conserved, 16-nucleotide (nt) C/U-rich element in this region (39,75,76). The cis-acting pyrimidine-rich element (PRE) assembles an mRNP "␣-complex" that compri...

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Hemoglobin Saverne: A New Variant with Elongated β Chains: Structural and Functional Properties

Cited by 26 publications

References 27 publications

Functional Studies on Nine Different Haemoglobins with High Oxygen Affinity

Functional Studies on Nine Different Haemoglobins with High Oxygen Affinity

Structural and Functional Analysis of an mRNP Complex That Mediates the High Stability of Human β-Globin mRNA

A Nucleolin-Binding 3′ Untranslated Region Element Stabilizes β-Globin mRNA In Vivo

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