Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.
Cell death & disease
Nature Publishing Group
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Johnson, T. I., Costa, A. S., Ferguson, A. N., & Frezza, C. (2018). Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.. Cell death & disease, 9 (9), 913. https://doi.org/10.1038/s41419-018-0912-3
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 suppress 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.
Cell Line, Tumor, Humans, Leiomyomatosis, Carcinoma, Renal Cell, Skin Neoplasms, Uterine Neoplasms, Kidney Neoplasms, Neoplastic Syndromes, Hereditary, DNA Damage, Genomic Instability, Fumarate Hydratase, Mitosis, G2 Phase, DNA Repair, Germ-Line Mutation, Radiation, Ionizing
MRC (MC_UU_12022/1_do not transfer?)
Medical Research Council (MC_UU_12022/6)
External DOI: https://doi.org/10.1038/s41419-018-0912-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284616
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/