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Nucleic Acids Research Advance Access published online on February 25, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp091
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© 2009 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.

Genome Integrity, Repair and Replication

Mice expressing an error-prone DNA polymerase in mitochondria display elevated replication pausing and chromosomal breakage at fragile sites of mitochondrial DNA

Laura J. Bailey1, Tricia J. Cluett1, Aurelio Reyes1, Tom A. Prolla2, Joanna Poulton3, Christiaan Leeuwenburgh4 and Ian J. Holt1,*

1MRC-Dunn Human Nutrition Unit, Wellcome Trust-MRC Building, Hills Road Cambridge, CB2 0XY, UK, 2Department of Genetics and Medical Genetics, University of Wisconsin, Madison, WI, 3Nuffield Department of Obstetrics and Gynaecology, The Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK and 4Institute on Aging, Department of Aging and Geriatrics College of Medicine, University of Florida, Gainesville, FL 32611, USA

*To whom correspondence should be addressed. Tel: 44 12 23 25 28 40; Fax: 44 12 23 25 28 45; Email: holt{at}mrc-dunn.cam.ac.uk

Received December 17, 2008. Revised January 29, 2009. Accepted February 4, 2009.

Expression of a proof-reading deficient form of mitochondrial DNA (mtDNA) polymerase {gamma}, POLG, causes early death accompanied by features of premature ageing in mouse. However, the mechanism of cellular senescence remains unresolved. In addition to high levels of point mutations of mtDNA, the POLG mutator mouse harbours linear mtDNAs. Using one- and two-dimensional agarose gel electrophoresis, we show that the linear mtDNAs derive from replication intermediates and are indicative of replication pausing and chromosomal breakage at the accompanying fragile sites. Replication fork arrest is not random but occurs at specific sites close to two cis-elements known as OH and OL. Pausing at these sites may be enhanced in the case of exonuclease-deficient POLG owing to delayed resumption of DNA replication, or replisome instability. In either case, the mtDNA replication cycle is perturbed and this might explain the progeroid features of the POLG mutator mouse.


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S. R. Bacman, S. L. Williams, and C. T. Moraes
Intra- and inter-molecular recombination of mitochondrial DNA after in vivo induction of multiple double-strand breaks
Nucleic Acids Res., July 1, 2009; 37(13): 4218 - 4226.
[Abstract] [Full Text] [PDF]


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