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Human Molecular Genetics Advance Access originally published online on September 19, 2007
Human Molecular Genetics 2007 16(24):3136-3148; doi:10.1093/hmg/ddm275
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© 2007 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.

Succinate inhibition of {alpha}-ketoglutarate-dependent enzymes in a yeast model of paraganglioma

Emily H. Smith, Ralf Janknecht and L. James Maher, III*

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, 200 First Street, SW, Rochester, MN 55905, USA

* To whom correspondence should be addressed. Tel: +1 5072849041; Fax: +1 5072842053; Email: maher{at}mayo.edu (J.M.)

Received August 8, 2007; Accepted September 14, 2007

The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a tumor suppressor. Heterozygosity for defective SDH subunit genes predisposes to familial paraganglioma (PGL) or pheochromocytoma (PHEO). Models invoking reactive oxygen species (ROS) or succinate accumulation have been proposed to explain the link between TCA cycle dysfunction and oncogenesis. Here we study the biochemical consequences of a common familial PGL-linked mutation, loss of the SDHB subunit, in a yeast model. This strain has increased ROS production but no evidence of mutagenic DNA damage. Because the strain lacks SDH activity, succinate accumulates dramatically and inhibits {alpha}-ketoglutarate ({alpha}KG)-dependent enzyme Jlp1, involved in sulfur metabolism, and {alpha}KG-dependent histone demethylase Jhd1. We show that mammalian JmjC-domain histone demethylases are also vulnerable to succinate inhibition in vitro and in cultured cells. Our results suggest that any {alpha}KG-dependent enzyme is a potential target of accumulated succinate in oncogenesis. The possible role that inhibition of these enzymes by succinate may have in oncogenesis is discussed.


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