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

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.

• Authors: Timothy I Johnson, Ana S H Costa, Ashley N Ferguson, Christian Frezza
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 9 Pg. 913 (09 06 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 30190474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fumarate Hydratase

Topics

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