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Molecular and Cellular Biology, August 2009, p. 4274-4282, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01834-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Dna2 Is a Nuclear and Mitochondrial DNA Maintenance Protein{triangledown} ,{dagger}

Julien P. Duxin,1 Benjamin Dao,1 Peter Martinsson,2 Nina Rajala,2 Lionel Guittat,1,# Judith L. Campbell,3 Johannes N. Spelbrink,2* and Sheila A. Stewart1,4*

Department of Cell Biology and Physiology,1 Institute of Medical Technology and Tampere University Hospital, Tampere, Finland,2 Braun Laboratories, California Institute of Technology, Pasadena, California,3 Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 631104

Received 2 December 2008/ Returned for modification 5 January 2009/ Accepted 20 May 2009

Dna2 is a highly conserved helicase/nuclease that in yeast participates in Okazaki fragment processing, DNA repair, and telomere maintenance. Here, we investigated the biological function of human Dna2 (hDna2). Immunofluorescence and biochemical fractionation studies demonstrated that hDna2 was present in both the nucleus and the mitochondria. Analysis of mitochondrial hDna2 revealed that it colocalized with a subfraction of DNA-containing mitochondrial nucleoids in unperturbed cells. Upon the expression of disease-associated mutant forms of the mitochondrial Twinkle helicase which induce DNA replication pausing/stalling, hDna2 accumulated within nucleoids. RNA interference-mediated depletion of hDna2 led to a modest decrease in mitochondrial DNA replication intermediates and inefficient repair of damaged mitochondrial DNA. Importantly, hDna2 depletion also resulted in the appearance of aneuploid cells and the formation of internuclear chromatin bridges, indicating that nuclear hDna2 plays a role in genomic DNA stability. Together, our data indicate that hDna2 is similar to its yeast counterpart and is a new addition to the growing list of proteins that participate in both nuclear and mitochondrial DNA maintenance.

* Corresponding author. Mailing address for Sheila A. Stewart: Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8228, St. Louis, MO 63110. Phone: (314) 362-7437. Fax: (314) 362-7463. E-mail: sheila.stewart{at}cellbiology.wustl.edu. Mailing address for Johannes N. Spelbrink: Institute of Medical Technology, FI-33014 University of Tampere, Tampere, Finland. Phone: 358 3 3551 8598. Fax: 358 3 3551 7710. E-mail: hans.spelbrink{at}uta.fi

{triangledown} Published ahead of print on 1 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

# Present address: INSERM U565, CNRS UMR 5153, USM 503 Muséum National d'Histoire Naturelle, Paris, France.

Molecular and Cellular Biology, August 2009, p. 4274-4282, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01834-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Stewart, J. A., Campbell, J. L., Bambara, R. A. (2009). Dna2 is a structure-specific nuclease, with affinity for 5'-flap intermediates. Nucleic Acids Res 0: gkp1055v1-gkp1055 [Abstract] [Full Text]  


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