Human Molecular Genetics Advance Access published online on July 22, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg238
© 2003 by Oxford University Press
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1 School of Neurology, Neurobiology and Psychiatry, Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom
* To whom correspondence should be addressed. E-mail: r.n.lightowlers{at}ncl.ac.uk.
Human mtDNA is transcribed from both strands, producing polycistronic RNA species that are immediately processed. Discrete RNA units are matured by the addition of nucleotides at their 3' termini: -CCA trinucleotide is added to mt-tRNAs, whilst mt-rRNAs and mt-mRNAs are oligo- or polyadenylated, respectively. The cis-acting elements, enzymes and indeed the mechanisms involved in these processes are still largely uncharacterised. Further, the function of polyadenylation in promoting stability, translation or decay of human mt-mRNA is unclear. A micro-deletion has been identified in a patient presenting with mtDNA disease. Loss of these two residues removes the termination codon for MTATP6 and sets MTCO3 immediately in frame. Accurate processing at this site still occurs, but there is a markedly decreased steady-state level of RNA14, the ATPase 8 and 6-encoding bi-cistronic mRNA unit, establishing that an mtDNA mutation can cause dysregulation of mRNA stability. Analysis of the polyadenylation profile of the processed RNA14 at steady-state revealed substantial abnormalities. The majority of mutated RNA14 terminated with short poly (A) extensions and a second, partially truncated population, was also present. Initial maturation of mutated RNA14 was unaffected, but deadenylation occurred rapidly. Inhibition of mitochondrial protein synthesis showed that the deadenylation was dependent on translation. Finally, deadenylation was shown to enhance mRNA decay, explaining the decrease in steady-state RNA14. An hypothesis is presented to describe how an mtDNA mutation that results in the loss of a termination codon, causes enhanced mt-mRNA decay by translation-dependent deadenylation.
Article
Investigation of a pathogenic mtDNA microdeletion reveals a translation-dependent deadenylation decay pathway in human mitochondria
2 Dept of Medical Genetics, AZ-VUB, Laarbeeklaan 101, B-1090 Brussels, Belgium
3 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Dept of Genetics University of Warsaw, Pawinskiego, 5A 02-106, Warsaw, Poland
4 Dept of Neurology, University of Bergen, Haukeland Sykehus, 5021, Bergen, Norway
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