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Human Molecular Genetics Advance Access originally published online on November 27, 2007
Human Molecular Genetics 2008 17(6):775-788; doi:10.1093/hmg/ddm349
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Transcriptional activators HAP/NF-Y rescue a cytochrome c oxidase defect in yeast and human cells

Flavia Fontanesi1, Can Jin3, Alexander Tzagoloff3 and Antoni Barrientos1,2,*

1 Department of Neurology 2 Department of Biochemistry & Molecular Biology, The John T. MacDonald Foundation Center for Medical Genetics, University of Miami Miller School of Medicine, Miami, FL, USA 3 Department of Biological Sciences, Columbia University, New York, NY, USA

* To whom correspondence should be addressed at: Department of Neurology and Biochemistry & Molecular Biology, The John T. Macdonald Center for Medical Genetics, Universtiy of Miami Miller School of Medicine, 1600 NW 10th Ave., RMSB # 2067, Miami, FL 33136, USA. Tel: +1 3052438683; Fax: +1 3052433914; Email: abarrientos{at}med.miami.edu

Received October 29, 2007; Accepted November 26, 2007

Cell survival and energy production requires a functional mitochondrial respiratory chain. Biogenesis of cytochrome c oxidase (COX), the last enzyme of the mitochondrial respiratory chain, is a very complicated process and requires the assistance of a large number of accessory factors. Defects in COX assembly alter cellular respiration and produce severe human encephalomyopathies. Mutations in SURF1, a COX assembly factor of exact unknown function, produce Leigh's syndrome (LS), the most frequent cause of COX deficiency in infants. In the yeast Saccharomyces cerevisiae, deletion of the SURF1 homologue SHY1 results in a similar COX deficiency. In order to identify genetic modifiers of the shy1 mutant phenotype, we have explored for genetic interactions involving SHY1. Here we report that overexpression of Hap4p, the catalytic subunit of the CCAAT binding transcriptional activator Hap2/3/4/5p complex, suppresses the respiratory defect of yeast shy1 mutants by increasing the expression of nuclear-encoded COX subunits that interact with the mitochondrially encoded Cox1p. Analogously, overexpression of the Hap complex human homologue NF-YA/B/C transcription complex in SURF1-deficient fibroblasts from an LS patient efficiently rescues their COX deficiency.


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