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 |
Appears in Collections: | Elements Staff Publications |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1371_journal_pbio_1000328.pdf | 1.99 MB | Adobe PDF | OPEN | None | View/Download |
This item is licensed under a Creative Commons License