Please use this identifier to cite or link to this item: https://doi.org/10.3389/fmolb.2018.00068
Title: Fumarase: From the TCA Cycle to DNA Damage Response and Tumor Suppression
Authors: Leshets, Michael
Silas, Yardena BH
Lehming, Norbert 
Pines, Ophry 
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
fumarase
DNA damage response
organic acids
mitochondria
protein dual targeting
tumor suppressor
metabolite signaling
DNA damage repair
STRAND-BREAK REPAIR
RENAL-CELL CANCER
SINGLE TRANSLATION PRODUCT
SACCHAROMYCES-CEREVISIAE
LIGASE-IV
HEREDITARY LEIOMYOMATOSIS
CUTANEOUS LEIOMYOMATOSIS
HOMOLOGOUS RECOMBINATION
UTERINE LEIOMYOMAS
END RESECTION
Issue Date: 25-Jul-2018
Publisher: FRONTIERS MEDIA SA
Citation: Leshets, Michael, Silas, Yardena BH, Lehming, Norbert, Pines, Ophry (2018-07-25). Fumarase: From the TCA Cycle to DNA Damage Response and Tumor Suppression. FRONTIERS IN MOLECULAR BIOSCIENCES 5. ScholarBank@NUS Repository. https://doi.org/10.3389/fmolb.2018.00068
Abstract: Fumarase is an enzyme of the tricarboxylic acid (TCA) cycle in mitochondria, but in recent years, it has emerged as a participant in the response to DNA double strand breaks (DSBs) in the nucleus. In fact, this enzyme is dual-targeted and can be also readily detected in the mitochondrial and cytosolic/nuclear compartments of all the eukaryotic organisms examined. Intriguingly, this evolutionary conserved cytosolic population of fumarase, its enzymatic activity and the associated metabolite fumarate, are required for the cellular DNA damage response (DDR) to double-strand breaks. Here we review findings from yeast and human cells regarding how fumarase and fumarate may precisely participate in the DNA damage response. In yeast, cytosolic fumarase is involved in the homologous recombination (HR) repair pathway, through its function in the DSB resection process. One target of this regulation is the resection enzyme Sae2. In human cells, fumarase is involved in the non-homologous end joining (NHEJ) repair pathway. Fumarase is phosphorylated by the DNA-dependent protein kinase (DNA-PK) complex, which induces the recruitment of fumarase to the DSB and local generation of fumarate. Fumarate inhibits the lysine demethylase 2B (KDM2B), thereby facilitating the dimethylation of histone H3, which leads to the repair of the break by the NHEJ pathway. Finally, we discuss the question how fumarase may function as a tumor suppressor via its metabolite substrate fumarate. We offer a number of models which can explain an apparent contradiction regarding how fumarate absence/accumulation, as a function of subcellular location and stage can determine tumorigenesis. Fumarate, on the one hand, a positive regulator of genome stability (its absence supports genome instability and tumorigenesis) and, on the other hand, its accumulation drives angiogenesis and proliferation (thereby supporting tumor establishment).
Source Title: FRONTIERS IN MOLECULAR BIOSCIENCES
URI: https://scholarbank.nus.edu.sg/handle/10635/155069
ISSN: 2296-889X
2296-889X
DOI: 10.3389/fmolb.2018.00068
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