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Bridging PNAs can bind preferentially to a deleted mitochondrial DNA template but replication by mitochondrial DNA polymerase γ in vitro is not impaired

Lookup NU author(s): Dr Paul Smith, Dr Gunther Ross, Professor Robert Taylor, Professor Doug Turnbull, Professor Robert Lightowlers

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Abstract

Mutations in mitochondrial DNA (mtDNA) are an important cause of neurological and other human pathologies. In the vast majority of cases, supportive care only is available. Mutated and wild-type mtDNAs often coexist in the same cell. A strategy for treatment has been proposed whereby replication of mutated mtDNA is inhibited by selective hybridisation of a nucleic acid derivative, allowing propagation of the wild-type genome and correction of the associated respiratory chain defect. Peptide nucleic acid molecules (PNAs) can be designed to selectively target pathogenic mtDNA with single point mutations. Molecules harbouring deletions present a complex problem. Deletions often occur between two short repeat sequences (4-13 residues), one of which is retained in the deleted molecule. With the more common large repeats, it is therefore difficult to design an antigenomic molecule that will bind selectively under physiological conditions. Following limited success with antigenomic oligodeoxynucleotides (ODNs), we have repeated these studies with a series of bridging PNAs. Molecules complementary to the sequence flanking either side of the 13 bp 'common deletion' were synthesised. The PNAs demonstrated markedly greater affinity for the delete than to the wild-type template. In runoff assays using Klenow fragment, these PNAs selectively inhibited replication of the delete template. However, no selective inhibition was observed when a polymerase γ-containing mitochondrial fraction was used. © 2003 Elsevier B.V. All rights reserved.


Publication metadata

Author(s): McGregor A, Smith PM, Ross GF, Taylor RW, Turnbull DM, Lightowlers RN

Publication type: Article

Publication status: Published

Journal: Biochimica et Biophysica Acta - Gene Structure and Expression

Year: 2003

Volume: 1629

Issue: 1-3

Pages: 73-83

ISSN (print): 0167-4781

ISSN (electronic): 1876-4320

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.bbaexp.2003.08.005

DOI: 10.1016/j.bbaexp.2003.08.005

PubMed id: 14522082


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