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A human mitochondri...
A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression
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Wilson, W. C. (author)
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Hornig-Do, H. T. (author)
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Bruni, F. (author)
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Chang, J. H. (author)
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Jourdain, A. A. (author)
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Martinou, J. C. (author)
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- Falkenberg, Maria, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Spahr, H. (author)
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- Larsson, N. G. (author)
- Karolinska Institutet
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Lewis, R. J. (author)
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Hewitt, L. (author)
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Basle, A. (author)
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Cross, H. E. (author)
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Tong, L. (author)
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Lebel, R. R. (author)
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Crosby, A. H. (author)
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Chrzanowska-Lightowlers, Z. M. A. (author)
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Lightowlers, R. N. (author)
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(creator_code:org_t)
- 2014-07-09
- 2014
- English.
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:23, s. 6345-6355
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Abstract
Subject headings
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- The p.N478D missense mutation in human mitochondrial poly(A) polymerase (mtPAP) has previously been implicated in a form of spastic ataxia with optic atrophy. In this study, we have investigated fibroblast cell lines established from family members. The homozygous mutation resulted in the loss of polyadenylation of all mitochondrial transcripts assessed; however, oligoadenylation was retained. Interestingly, this had differential effects on transcript stability that were dependent on the particular species of transcript. These changes were accompanied by a severe loss of oxidative phosphorylation complexes I and IV, and perturbation of de novo mitochondrial protein synthesis. Decreases in transcript polyadenylation and in respiratory chain complexes were effectively rescued by overexpression of wild-type mtPAP. Both mutated and wild-type mtPAP localized to the mitochondrial RNA-processing granules thereby eliminating mislocalization as a cause of defective polyadenylation. In vitro polyadenylation assays revealed severely compromised activity by the mutated protein, which generated only short oligo(A) extensions on RNA substrates, irrespective of RNA secondary structure. The addition of LRPPRC/SLIRP, a mitochondrial RNA-binding complex, enhanced activity of the wild-type mtPAP resulting in increased overall tail length. The LRPPRC/SLIRP effect although present was less marked with mutated mtPAP, independent of RNA secondary structure. We conclude that (i) the polymerase activity of mtPAP can be modulated by the presence of LRPPRC/SLIRP, (ii) N478D mtPAP mutation decreases polymerase activity and (iii) the alteration in poly(A) length is sufficient to cause dysregulation of post-transcriptional expression and the pathogenic lack of respiratory chain complexes.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- RESPIRATORY-CHAIN COMPLEXES
- MESSENGER-RNA STABILITY
- POLYNUCLEOTIDE
- PHOSPHORYLASE
- POLY(A)-BINDING PROTEIN
- POLYADENYLATION
- TRANSLATION
- DECAY
- IDENTIFICATION
- SPECIFICITY
- INHIBITION
- Biochemistry & Molecular Biology
- Genetics & Heredity
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Wilson, W. C.
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Hornig-Do, H. T.
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Bruni, F.
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Chang, J. H.
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Jourdain, A. A.
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Martinou, J. C.
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show more...
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Falkenberg, Mari ...
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Spahr, H.
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Larsson, N. G.
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Lewis, R. J.
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Hewitt, L.
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Basle, A.
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Cross, H. E.
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Tong, L.
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Lebel, R. R.
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Crosby, A. H.
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Chrzanowska-Ligh ...
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Lightowlers, R. ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Human Molecular ...
- By the university
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University of Gothenburg
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Karolinska Institutet