Fumarase: From the TCA Cycle to DNA Damage Response and Tumor Suppression

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).

Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants

“…The observation that no UL had two SNVs/indels, points to an initial FH mutation (SNV/indel or CNV) in a progenitor cell which then increased the probability for a CN-loss in descendent cells. Fumarase is known to play a role in response to double strand-breaks (DSB) by activating the non-homologous end joining (NHEJ) mechanism [ 56 ]. When the NHEJ pathway is inactivated the DSB are repaired by more error prone mechanisms, like microhomology-mediated end joining, which can lead to deletions.…”

Longitudinal serum biomarker screening identifies malate dehydrogenase 2 as candidate prognostic biomarker for Duchenne muscular dystrophy

“…While it seems plausible that the reduction of MDH2 is linked to reduced mitochondrial capacity, the increase in FH may be related to another mechanism. It has been recently demonstrated that the role of FH is not only to produce reducing equivalents as part of the TCA cycle, but it also plays a role in DNA damage response; recently, telomeres length and DNA damage response in non‐dividing cardiomyocytes have been connected to cardiomyopathy, thus suggesting that FH serum level could be associated to cardiac involvement in DMD . Another protein increasing with age was RELB, which is a member of the alternative NF‐κB complex and is known to promote mitochondrial biogenesis and transition from a glycolytic towards an oxidative metabolism in muscle fibres .…”

TCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma

“…Moreover, FH is also involved in the response to the nuclear DNA double strand breaks [108] to maintain genomic stability [109]. Consequently, FH inactivation takes part in cancer development by inducing a loss of genome integrity.…”