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

Timothy I Johnson,Ana S H Costa,Ashley N Ferguson,Christian Frezza

doi:10.1038/s41419-018-0912-3

Abstract

An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of fumarate. Recent data indicate that, in FH-deficient cells, fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by ionising radiation (IR), and promotes early mitotic entry after IR in a fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.

Highlights

Fumarate hydratase (FH) is a nuclear-encoded metabolic enzyme that catalyses the reversible conversion of fumarate to malate in the mitochondria and cytosol
FH participates in the tricarboxylic acid (TCA) cycle, whereas in the cytosol it buffers fumarate produced from cytosolic reactions such as during purine biosynthesis and from the production of arginine from argininosuccinate in the urea cycle
These results indicate that FH-deficient cells exhibit a faster mitotic progression that contributes to the diminished G2/ M accumulation upon ionising radiation (IR)

Summary

Introduction

Fumarate hydratase (FH) is a nuclear-encoded metabolic enzyme that catalyses the reversible conversion of fumarate to malate in the mitochondria and cytosol. FH participates in the tricarboxylic acid (TCA) cycle, whereas in the cytosol it buffers fumarate produced from cytosolic reactions such as during purine biosynthesis and from the production of arginine from argininosuccinate in the urea cycle. FH loss leads to hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by benign smooth muscle tumours in the skin and uterus, and type II papillary renal cancer[1]. Fumarate was shown to inhibit various αKG-dependent dioxygenases, such as the hypoxia inducible factor (HIF) prolyl hydroxylases[2] and histone and DNA demethylases[3,4] leading to profound epigenetic changes associated with tumour formation

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