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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Johnson, Timothy I 
Costa, Ana SH 
Ferguson, Ashley N 

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.

Description

Keywords

Carcinoma, Renal Cell, Cell Line, Tumor, DNA Damage, DNA Repair, Fumarate Hydratase, G2 Phase, Genomic Instability, Germ-Line Mutation, Humans, Kidney Neoplasms, Leiomyomatosis, Mitosis, Neoplastic Syndromes, Hereditary, Radiation, Ionizing, Skin Neoplasms, Uterine Neoplasms

Journal Title

Cell Death Dis

Conference Name

Journal ISSN

2041-4889
2041-4889

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
MRC (unknown)
Medical Research Council (MC_UU_12022/6)