Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pbio.1000328
Title: Fumarase: A mitochondrial metabolic enzyme and a cytosolic/nuclear component of the dna damage response
Authors: Yogev O.
Yogev O.
Singer E.
Shaulian E.
Goldberg M.
Fox T.D.
Pines O. 
Keywords: fumarate hydratase
fumaric acid
hypoxia inducible factor
fumarate hydratase
fumaric acid derivative
histone
hypoxia inducible factor 1alpha
isoenzyme
Saccharomyces cerevisiae protein
tumor suppressor protein
article
cancer cell culture
carcinogenesis
cell protection
controlled study
cytosol
DNA metabolism
double stranded DNA break
enzyme activity
fungal strain
gene construct
gene function
gene location
glucose metabolism
human
human cell
mitochondrion
molecular interaction
molecular recognition
tumor suppressor gene
yeast
cell nucleus
cytosol
DNA damage
enzymology
gene silencing
genetics
HeLa cell
kidney tumor
leiomyomatosis
metabolism
mitochondrion
Saccharomyces cerevisiae
Eukaryota
Cell Nucleus
Cytosol
DNA Damage
Fumarate Hydratase
Fumarates
Gene Knockdown Techniques
Hela Cells
Histones
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Isoenzymes
Kidney Neoplasms
Leiomyomatosis
Mitochondria
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Tumor Suppressor Proteins
Issue Date: 2010
Citation: Yogev O., Yogev O., Singer E., Shaulian E., Goldberg M., Fox T.D., Pines O. (2010). Fumarase: A mitochondrial metabolic enzyme and a cytosolic/nuclear component of the dna damage response. PLoS Biology 8 (3). ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pbio.1000328
Rights: Attribution 4.0 International
Abstract: In eukaryotes, fumarase (FH in human) is a well-known tricarboxylic-acid-cycle enzyme in the mitochondrial matrix. However, conserved from yeast to humans is a cytosolic isoenzyme of fumarase whose function in this compartment remains obscure. A few years ago, FH was surprisingly shown to underlie a tumor susceptibility syndrome, Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). A biallelic inactivation of FH has been detected in almost all HLRCC tumors, and therefore FH was suggested to function as a tumor suppressor. Recently it was suggested that FH inhibition leads to elevated intracellular fumarate, which in turn acts as a competitive inhibitor of HPH (HIF prolyl hydroxylase), thereby causing stabilization of HIF (Hypoxia-inducible factor) by preventing proteasomal degradation. The transcription factor HIF increases the expression of angiogenesis regulated genes, such as VEGF, which can lead to high microvessel density and tumorigenesis. Yet this mechanism does not fully explain the large cytosolic population of fumarase molecules. We constructed a yeast strain in which fumarase is localized exclusively to mitochondria. This led to the discovery that the yeast cytosolic fumarase plays a key role in the protection of cells from DNA damage, particularly from DNA double-strand breaks. We show that the cytosolic fumarase is a member of the DNA damage response that is recruited from the cytosol to the nucleus upon DNA damage induction. This function of fumarase depends on its enzymatic activity, and its absence in cells can be complemented by high concentrations of fumaric acid. Our findings suggest that fumarase and fumaric acid are critical elements of the DNA damage response, which underlies the tumor suppressor role of fumarase in human cells and which is most probably HIF independent. This study shows an exciting crosstalk between primary metabolism and the DNA damage response, thereby providing a scenario for metabolic control of tumor propagation. © 2010 Yogev et al.
Source Title: PLoS Biology
URI: https://scholarbank.nus.edu.sg/handle/10635/161665
ISSN: 15449173
DOI: 10.1371/journal.pbio.1000328
Rights: Attribution 4.0 International
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