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).
Highlights
The maintenance of genome integrity is one of the most important problems of all living organisms
Fumarase is a highly conserved metabolic enzyme of the tricarboxylic acid (TCA) cycle which is involved in the two main double-strand breaks (DSBs) repair pathways in eukaryotes; non-homologous end joining (NHEJ) in human and homologous recombination (HR) in yeast
The enzyme and its associated metabolite fumarate, interact and affect different components of the DNA damage response (DDR) pathways (e.g., ketoglutarate-dependent lysine demethylase 2B (KDM2B), Sae2, Figure 2A, 3). To this setting we can add a recent study by Singer et al which shows that fumarase in prokaryotes already possessed both TCA cycle and DDR functions (Singer et al, 2017)
Summary
The maintenance of genome integrity is one of the most important problems of all living organisms. In the course of translation, a subset of FUM1 translation products, which are partially translocated, fold outside mitochondria and are blocked for full mitochondrial import by a mechanism termed reverse translocation (Figure 1, right, S. cerevisiae) Upon translation termination, these folded translation products remain in the cytosol constituting the cytosolic fumarase population (Stein et al, 1994; Sass et al, 2001, 2003; Yogev and Pines, 2011; Kalderon and Pines, 2014). Fumarase knockdown has been shown to increase cell susceptibility to ionizing radiation and hydroxyurea (HU) induced DSBs (Yogev et al, 2010) These results from human and yeast cells were the basis for our original model of fumarase function in the DDR (Figure 2A). The dual function of fumarase in the TCA cycle and the DDR may be an ancient feature of prokaryotes and eukaryotes
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