Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation

Johnson, Timothy Isaac; Costa, Ana S.H.; Ferguson, Ashley N.; Frezza, Christian

doi:10.1038/s41419-018-0912-3

Cited by 30 publications

(30 citation statements)

References 22 publications

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“…For instance, it has been shown that FH loss alters the activation of the AMP-activated protein kinase (AMPK) [92], the mammalian target of rapamycin (mTOR) [92] and Abelson murine leukaemia viral oncogene homolog 1 (ABL-1) [93,94]. Furthermore, FH-deficient cells exhibit alterations of the cyclic AMP (cAMP) [95] signalling and DNA-damage response (DDR) pathway [96,97]. The role of these cascades in FH-deficient cells will be briefly described in this section below (Fig.…”

Section: Other Molecular Cascades Affected By Fh Lossmentioning

confidence: 99%

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Schmidt

Sciacovelli

Frezza

2020

Seminars in Cell & Developmental Biology

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103

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Cancer is now considered a multifactorial disorder with different aetiologies and outcomes. Yet, all cancers share some common molecular features. Among these, the reprogramming of cellular metabolism has emerged as a key player in tumour initiation and progression. The finding that metabolic enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH), when mutated, cause cancer suggested that metabolic dysregulation is not only a consequence of oncogenic transformation, but that it can act as cancer driver. However, the mechanisms underpinning the link between metabolic dysregulation and cancer remain only partially understood. In this review we discuss the role of FH loss in tumorigenesis, focusing on the role of fumarate as a key activator of a variety of oncogenic cascades. We also discuss how these alterations are integrated and converge towards common biological processes. This review highlights the complexity of the signals elicited by FH loss, describes that fumarate can act as a bona fide oncogenic event, and provides a compelling hypothesis of the step wise neoplastic progression after FH loss.

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Section: Other Molecular Cascades Affected By Fh Lossmentioning

confidence: 99%

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Schmidt

Sciacovelli

Frezza

2020

Seminars in Cell & Developmental Biology

Self Cite

103

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“…The best example is the enzyme fumarase (fumarate hydratase) which belongs to Class-II (FumC-like fumarases). This TCA cycle enzyme has been shown to be involved in the DNA damage response in yeast and human, and more recently in the Gram-positive bacterium B. subtilis (Jiang et al, 2018; Johnson, Costa, Ferguson, & Frezza, 2018; Leshets et al, 2018; Singer et al, 2017). In human and yeast, fumarate (fumaric acid) is the signalling molecule targeting histone demethylases and a HRR resection enzyme respectively (Jiang et al, 2018; Leshets et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Fe-(II)/α-KG-dependent dioxygenases are present in all living organisms and catalyse hydroxylation reactions on a diverse set of substrates, including proteins, alkylated DNA/RNA, lipids and others (Hausinger, 2004; Loenarz & Schofield, 2008). Fumarate and its precursor succinate have been shown to inhibit a variety of Fe-(II)/α-KG-dependent dioxygenases, and this inhibition was shown to antagonize α-KG-dependent processes and negatively regulate Fe-(II)/α-KG-dependent dioxygenases such as prolyl hydroxylases (PHDs), histone lysine demethylases (KDMs), collagen prolyl-4-hydroxylases, and the TET (ten-eleven translocation) family of 5-methlycytosine (5mC) hydroxylases (Gottlieb & Tomlinson, 2005; Jiang et al, 2018; Johnson et al, 2018; Pollard et al, 2005; Selak et al, 2005; Tahiliani et al, 2009; Xiao et al, 2012). We find, in agreement with the above observations, that AlkB enzymatic activity is inhibited by the presence of high concentrations of fumarate and succinate both in vitro and in vivo, indicating that AlkB inhibition has a specific consequence in vivo, leading to the sensitivity of ΔfumA, ΔfumB and ΔfumACB to DNA damage.…”

Section: Discussionmentioning

confidence: 99%

A novel combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in E. coli

Silas

Singer

Lehming

et al. 2020

Preprint

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Class-II fumarase (Fumarate Hydratase, FH) and its metabolic intermediates are essential components in the DNA damage response (DDR) in eukaryotic cells (human and yeast) and in the prokaryote Bacillus subtilis. Strikingly, here we show, in Escherichia coli, which harbors three fumarase genes; Class-I fumA and fumB and Class-II fumC, a variation of the distribution of function so far demonstrated (TCA cycle and DDR). Contrary to previous reports, E. coli Class-II fumarase participates naturally in respiration and the Class-I fumarases in the DDR. Contrary to other organisms, in E. coli, alpha-ketoglutarate (α-KG) is the organic acid that complements DNA damage sensitivity of fum null mutants. We show inhibition of the α-KG-dependent DNA damage repair enzyme, AlkB, by fumarate and succinate, and a global effect of fumarase absence on transcription. Together these results show an adaptable metabolic signalling of the DDR during evolution regardless of the enzyme Class preforming the DDR related function.

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“…Similar to 2HG, they inhibit α-KG dioxygenases, such as KDM4A/B, increasing basal level of H3K9me3, and lead to a defect in HR [182,183]. Moreover, fumarate accumulation, in the context of FH deficiency, leads to a bypass of checkpoint maintenance, thus inducing endogenous DNA damage and increasing resistance to IR [184]. However, local production of fumarate by FH, which catalyzes the reversible reaction of fumarate to malate, has also been shown to enhance NHEJ.…”

Section: Metabolic Regulation Of Epigenetic Marks Influences Dsb Repairmentioning

confidence: 99%

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Moretton

Loizou

2020

Cancers

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Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

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Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation

Cited by 30 publications

References 22 publications

Fumarate hydratase in cancer: A multifaceted tumour suppressor

Fumarate hydratase in cancer: A multifaceted tumour suppressor

A novel combination of Class-I fumarases and metabolites (α-ketoglutarate and fumarate) signal the DNA damage response in E. coli

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

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