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Nucleic Acids Research Advance Access published online on October 24, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl703
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Alterations to the expression level of mitochondrial transcription factor A, TFAM, modify the mode of mitochondrial DNA replication in cultured human cells

Jaakko L. O. Pohjoismäki1, Sjoerd Wanrooij1, Anne K. Hyvärinen1, Steffi Goffart1, Ian J. Holt2, Johannes N. Spelbrink1 and Howard T. Jacobs1,3,*

1 Institute of Medical Technology and Tampere University Hospital FI-33014 University of Tampere, Finland 2 MRC-Dunn Human Nutrition Unit, Hill Road Cambridge CB2 2XY, England, UK 3 IBLS Division of Molecular Genetics, University of Glasgow Glasgow G12 8QQ, Scotland, UK

*To whom correspondence should be addressed. Tel: +358 33 55 17 731; Fax: +358 32 15 77 10; Email: howard.t.jacobs{at}uta.fi

Received July 17, 2006. Revised September 8, 2006. Accepted September 11, 2006.

Mitochondrial transcription factor A (TFAM) is an abundant mitochondrial protein of the HMG superfamily, with various putative roles in mitochondrial DNA (mtDNA) metabolism. In this study we have investigated the effects on mtDNA replication of manipulating TFAM expression in cultured human cells. Mammalian mtDNA replication intermediates (RIs) fall into two classes, whose mechanistic relationship is not properly understood. One class is characterized by extensive RNA incorporation on the lagging strand, whereas the other has the structure of products of conventional, strand-coupled replication. TFAM overexpression increased the overall abundance of RIs and shifted them substantially towards those of the conventional, strand-coupled type. The shift was most pronounced in the rDNA region and at various replication pause sites and was accompanied by a drop in the relative amount of replication-termination intermediates, a substantial reduction in mitochondrial transcripts, mtDNA decatenation and progressive copy number depletion. TFAM overexpression could be partially phenocopied by treatment of cells with dideoxycytidine, suggesting that its effects are partially attributable to a decreased rate of fork progression. TFAM knockdown also resulted in mtDNA depletion, but RIs remained mainly of the ribosubstituted type, although termination intermediates were enhanced. We propose that TFAM influences the mode of mtDNA replication via its combined effects on different aspects of mtDNA metabolism.


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