Nucleic Acids Research, 2003, Vol. 31, No. 14 3909-3917
© 2003 Oxford University Press
Mitochondria-mediated nuclear mutator phenotype in Saccharomyces cerevisiae
1 Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231, USA, 2 Department of Life Sciences and Chemistry, Roskilde University, 4000 Roskilde, Denmark and 3 Department of Cancer Genetics, Roswell Park Cancer Institute, Cell and Virus Building, Elm and Carlton Streets, Buffalo, NY 14263, USA
*To whom correspondence should be addressed at Department of Cancer Genetics, Roswell Park Cancer Institute, Cell and Virus Building, Elm and Carlton Streets, Buffalo, NY 14263, USA. Tel: +1 716 845 8017; Fax: +1 716 845 1047; Email: keshav.singh{at}roswellpark.org
Using Saccharomyces cerevisiae as a model organism, we analyzed the consequences of disrupting mitochondrial function on mutagenesis of the nuclear genome. We measured the frequency of canavanine-resistant colonies as a measure of nuclear mutator phenotype. Our data suggest that mitochondrial dysfunction leads to a nuclear mutator phenotype (i) when oxidative phosphorylation is blocked in wild-type yeast at mitochondrial complex III by antimycin A and (ii) in mutant strains lacking the entire mitochondrial genome (rho0) or those with deleted mitochondrial DNA (rho–). The nuclear mutation frequencies obtained for antimycin A-treated cells as well as for rho– and rho0 cells were 
2- to 3-fold higher compared to untreated control and wild-type cells, respectively. Blockage of oxidative phosphorylation by antimycin A treatment led to increased intracellular levels of reactive oxygen species (ROS). In contrast, inactivation of mitochondrial activity (rho– and rho0) led to decreased intracellular levels of ROS. We also demonstrate that in rho0 cells the REV1, REV3 and REV7 gene products, all implicated in error-prone translesion DNA synthesis (TLS), mediate mutagenesis in the nuclear genome. However, TLS was not involved in nuclear DNA mutagenesis caused by inhibition of mitochondrial function by antimycin A. Together, our data suggest that mitochondrial dysfunction is mutagenic and multiple pathways are involved in this nuclear mutator phenotype.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E. H. Smith, R. Janknecht, and L. J. Maher III Succinate inhibition of {alpha}-ketoglutarate-dependent enzymes in a yeast model of paraganglioma Hum. Mol. Genet., December 15, 2007; 16(24): 3136 - 3148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhang, A. Chatterjee, and K. K. Singh Saccharomyces cerevisiae Polymerase {zeta} Functions in Mitochondria Genetics, April 1, 2006; 172(4): 2683 - 2688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Doudican, B. Song, G. S. Shadel, and P. W. Doetsch Oxidative DNA Damage Causes Mitochondrial Genomic Instability in Saccharomyces cerevisiae Mol. Cell. Biol., June 15, 2005; 25(12): 5196 - 5204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.A. Stuart, K. Hashiguchi, D.M. Wilson III, W.C. Copeland, N.C. Souza-Pinto, and V.A. Bohr DNA base excision repair activities and pathway function in mitochondrial and cellular lysates from cells lacking mitochondrial DNA Nucleic Acids Res., April 23, 2004; 32(7): 2181 - 2192. [Abstract] [Full Text] [PDF]
|
|