Fumarase: A Mitochondrial Metabolic Enzyme and a Cytosolic/Nuclear Component of the DNA Damage Response
Open accessAbstract
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.
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From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [115]
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A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
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“Though considered a Krebs cycle enzyme, FH is also expressed in the cytosol and the nucleus (Yogev et al., 2010, 2011).”
BackgroundO-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency
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“A lack of Fum1 can be complemented by high concentrations of its product, fumaric acid [177].”
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“(d) Immunoblot demonstrating that uncleaved wild type COQ7 (WT) migrates at the same position as COQ7 S36A (containing a point mutation in the predicted mitochondrial processing peptidase cleavage site) and that cleaved COQ7 migrates at the same position as COQ7(37-217) that lacks the N-terminal region cleaved by MPP.”
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“The cytosolic isoform of fumarase plays a role in DNA repair by translocating from the cytoplasm to nucleus [54].”
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“It has been reported that fumarase is involved in DNA repair (70).”
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“[1] To date, the enzyme is known to carry out two distinct functions: the TCA cycle, the DNA damage response pathway (DDR) (Figure 1).[2] In humans, FH is encoded by the fumarate hydratase gene (FH), located on the q-arm of chromosome 1 (chr1q43).”
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“A good example is the single translation product of yeast fumarase, an enzyme of the TCA cycle in mitochondria and a protein whose enzymatic activity is involved in the DNA damage response in the cytosol/nucleus [30].”
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“Fumarase, a mitochondrial metabolic enzyme involved in the tricarboxylic acid cycle, is localized to the nucleus in response to DNA damage and exhibits a metabolically dependent role in maintaining genomic integrity (Yogev et al., 2010).”
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“An example of this is fumarase, a metabolic enzyme from the tricarboxylic acid cycle, whose absence may increase intracellular levels of fumarate, making yeast cells more sensitive to stresses producing double-strand breaks in DNA (105, 106).”
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“Fumarate can increase histone H3 methylation by inhibiting KDM2B demethylase and promote binding of DNA-dependent protein kinase and the recruitment of end-processing enzymes for DNA repair [101,106,107].”
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“In a seminal study, Yogev and colleagues (Yogev et al. 2010) recently employed S.”
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“FH is found in the cytosol and mitochondria of all eukaryotes (Kornberg and Krebs, 1957), but its nuclear localization was first discovered in yeast (Yogev et al., 2010).”
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“The second model, suggests that the loss of fumarase diminishes the ability of the cell to generate fumarate, thereby compromising genomic stability (Yogev et al., 2010; Jiang et al., 2015).”
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“Fumarase and fumaric acid are probably 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 (Yogev et al., 2010).”
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“For example, fumarase participates in the tricarboxylic acid cycle when in the mitochondria, and in the DNA damage response when in the cytosol and nucleus (Yogev et al., 2010).”
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“In addition, cytosolic FH has been implicated in the DNA damage response [30].”
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“In the nucleus, the bidirectional enzyme fumarase converts malate to fumarate, leading to increased levels of nuclear fumarate (67) that compete with α-KG to inhibit the lysinespecific demethylase 2A (KDM2A), resulting in stabilization and higher levels of histone H3K36me2.”
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“The tricarboxylic acid cycle enzyme, fumarase, could be recruited to the nucleus upon DNA damage induction and has an apparent role in DNA repair [47].”
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“The enzyme fumarase (FH) is conserved among species and represents a well-known paradigm for dual targeted proteins (Yogev et al., 2010, 2011).”
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Human Fumarate Hydratase Is Dual Localized by an Alternative Transcription Initiation Mechanism
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“We discovered that extra-mitochondrial fumarase is required for protection from double strand breaks, as part of the DNA damage response (DDR), both in yeast and human (10).”
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“Although the purpose of the cytosolic type is not well-defined, it is theorized to be implicated in amino acid metabolism, the DNA damage response, or the stabilization of tumorigenic hypoxia inducible factor (HIF) [61–63].”
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“3 Fumarase Fumarase has been recently shown to underlie a tumor susceptibility syndrome, functioning as a tumor suppressor [41].”
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“Fumarate hydratase, which only exists in one form, is most commonly located in the mitochondria but can be found in the cytoplasm and can translocate to the nucleus upon DNA damage [33].”
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Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues
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Renal cell carcinoma: translational aspects of metabolism and therapeutic consequences
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Structural, biochemical and biophysical characterization of recombinant human fumarate hydratase
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Oncometabolites—A Link between Cancer Cells and Tumor Microenvironment
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“The loss of function of FH is associated with multiple compensatory metabolic changes, mitochondrial impairment, and the intracellular accumulation of fumarate, as well as an increased sensitivity to DNA damage, which is associated with pseudohypoxia and tumor aggressiveness [10,88].”
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“Finally, fumarase has been proposed to act as a tumor suppressor [25].”
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Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2
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“Moreover, FH enzymatic activity is required for the cellular DNA damage response to double-strand breaks, and it is known that it is involved in the non-homologous end joining repair pathway [125,126].”
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“It is worth noting that the cytosolic isoenzyme FH can be recruited to the nucleus in response to DNA damage, contributing to cancer cell survival (186).”
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“Another parallel for Lys20, in terms of DNA repair, may be the Krebs cycle enzyme fumarase, which was discovered recently to have DNA repair functions dependent on its catalytic activity (Yogev et al. 2010).”
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Bacterial fumarase and L-malic acid are evolutionary ancient components of the DNA damage response
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“Fumarase is a dual targeted protein in eukaryotes; its echoforms are distributed between mitochondria and the cytosol/nucleus (Yogev et al., 2011; Yogev et al., 2010).”
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“The distribution of fumarase activity between the mitochondria and cytosol in many organisms is approximately equal, or the mitochondrial form prevails, as in the current study [29].”
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Fumarate Esters as Angiogenesis Inhibitors: Key to Action in Psoriasis?
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“An elevated HIF drives the transcription of key components of the glycolytic pathway, including GLUT1 and LDH, inducing the Warburg effect (the tendency of cancer cells to rely on glycolysis as their energy source). However, there are probably other tumor suppressor roles of FH that are probably HIF independent and in…”
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“In addition, cytosolic FH can migrate from the cytosol to the nucleus, where it plays a key role in DNA repair (3).”
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“2), is an enzyme that catalyzes the reversible hydration of fumarate to (S)-malate in the mitochondrion in eukaryotes, as a component of the tricarboxylic acid cycle (40), and promotion of histone H3 methylation and DNA repair in the cytosol (41).”
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- Authors
- Yogev, O., Yogev, O., Singer, E., Shaulian, E., Goldberg, M., Fox, T. D., & Pines, O.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Cornell University (US)
- Corresponding author
- Pines, Ophry
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-03-09
- Volume
- 8
- Issue
- 3
- Pages
- e1000328
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC2834712
- OpenAlex
- W2011300705
- Semantic Scholar
- 78a618ae76fed75bb98e6065698b484343ba0690
- Cited by
- 220
- References
- 39
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 15 · 2021: 23 · 2020: 16 · 2019: 22 · 2018: 11 · 2017: 11 · 2016: 12 · 2015: 10 · 2014: 7 · 2013: 16 · 2012: 8
- FWCI
- 6.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Israel Science Foundation
- National Institutes of Health
- National Institute of General Medical Sciences (GM-29362, R01GM029362)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- fumarase, DNA damage response, DNA double-strand breaks, tumor suppressor, hereditary leiomyomatosis and renal cell carcinoma, fumaric acid, HIF prolyl hydroxylase, hypoxia-inducible factor, mitochondrial metabolism, primary metabolism
- MeSH terms
- Cell Nucleus, Cytosol, DNA Damage, Fumarate Hydratase, Fumarates, HeLa Cells, Histones, Humans, Isoenzymes, Kidney Neoplasms, Mitochondria, Saccharomyces cerevisiae, Leiomyomatosis, Tumor Suppressor Proteins, Saccharomyces cerevisiae Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Gene Knockdown Techniques
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