Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Almost all IDH1/2 mutations occur in a few unique locations in the active site, resulting in neomorphic activity converting α-KG to D-2-HG.
“Remarkably, almost all IDH1/2 mutations occur in a few unique locations in the active site of the enzymes, which results in the acquirement of a neomorphic enzymatic activity converting α-KG to the oncometabolite D-2-HG118-120.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [118]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Oxidative DNA damage: mechanisms, mutation, and disease
Cooke, M. S., Evans, M. D., Dizdaroglu, M., & Lunec, J. (2003) · The FASEB Journal · doi:10.1096/fj.02-0752rev · Cited by 3,245 · see citing works
The Multiple Leiomyoma Consortium (2002) · Nature Genetics · doi:10.1038/ng849 · Cited by 1,635 · see citing works
Playing the End Game: DNA Double-Strand Break Repair Pathway Choice
Chapman, J. R., Taylor, M. R. G., & Boulton, S. J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.07.029 · Cited by 1,622 · see citing works
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · see citing works
Regulation of mammalian nucleotide metabolism and biosynthesis
Lane, A. N., & Fan, T. W.-M. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv047 · Cited by 959 · see citing works
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
Nucleotide deficiency promotes genomic instability in early stages of cancer development
Bester, A. C., Roniger, M., Oren, Y. S., Im, M. M., Sarni, D., Chaoat, M., Bensimon, A., Zamir, G., Shewach, D. S., & Kerem, B. (2011) · Cell · doi:10.1016/j.cell.2011.03.044 · Cited by 858 · see citing works
Lukas, C., Savic, V., Bekker‐Jensen, S., Doil, C., Neumann, B., Pedersen, R. S., Grøfte, M., Chan, K., Hickson, I. D., Bártek, J., et al. (2011) · Nature Cell Biology · doi:10.1038/ncb2201 · Cited by 658 · see citing works
The impact of a negligent G2/M checkpoint on genomic instability and cancer induction
Löbrich, M., & Jeggo, P. A. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2248 · Cited by 627 · see citing works
Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition
Sciacovelli, M., Gonçalves, E., Johnson, T. I., Zecchini, V. R., da Costa, A. S. H., Gaude, E., Drubbel, A. V., Theobald, S. J., Abbo, S. R., Tran, M. G. B., et al. (2016) · Nature · doi:10.1038/nature19353 · Cited by 584 · see citing works
Self-citationReplication stress induces 53BP1-containing OPT domains in G1 cells
Harrigan, J. A., Belotserkovskaya, R., Coates, J., Dimitrova, D. S., Polo, S. E., Bradshaw, C. R., Fraser, P., & Jackson, S. P. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201011083 · Cited by 336 · see citing works
The bromodomain protein Brd4 insulates chromatin from DNA damage signalling
Floyd, S., Pacold, M. E., Huang, Q., Clarke, S. M., Lam, F. C., Cannell, I. G., Bryson, B. D., Rameseder, J., Lee, M. J., Blake, E. J., et al. (2013) · Nature · doi:10.1038/nature12147 · Cited by 324 · see citing works
Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination
Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., Yuan, S., Viney, I., Zhao, S., Carrer, A., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.008 · Cited by 295 · see citing works
Yogev, O., Yogev, O., Singer, E., Shaulian, E., Goldberg, M., Fox, T. D., & Pines, O. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000328 · Cited by 220 · see citing works
Sulkowski, P. L., Sundaram, R. K., Oeck, S., Corso, C. D., Liu, Y., Noorbakhsh, S., Niger, M., Boeke, M., Ueno, D., Kalathil, A. N., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0170-4 · Cited by 213 · see citing works
Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation
Jiang, Y., Qian, X., Shen, J., Wang, Y., Li, X., Liu, R., Xia, Y., Chen, Q., Peng, G., Lin, S.-Y., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3209 · Cited by 208 · see citing works
Lallo, A., Frese, K. K., Morrow, C. J., Sloane, R. A. S., Gulati, S., Schenk, M. W., Trapani, F., Simms, N., Galvin, M., Brown, S., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2805 · Cited by 156 · see citing works
Diseases Associated with Defective Responses to DNA DamagePreprint
O’Driscoll, M. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a012773 · Cited by 139 · see citing works
Yang, Y., Valera, V., Padilla‐Nash, H. M., Sourbier, C., Vocke, C. D., Vira, M. A., Abu-Asab, M. S., Bratslavsky, G., Tsokos, M., Merino, M. J., et al. (2009) · Cancer Genetics and Cytogenetics · doi:10.1016/j.cancergencyto.2009.08.018 · Cited by 138 · see citing works
Blatnik, M., Thorpe, S. R., & Baynes, J. W. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1433.047 · Cited by 109 · see citing works
A role for cytosolic fumarate hydratase in urea cycle metabolism and renal neoplasia
Adam, J., Yang, M., Bauerschmidt, C., Kitagawa, M., O’Flaherty, L., Maheswaran, P., Özkan, G., Sahgal, N., Baban, D., Kato, K., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.04.006 · Cited by 97 · see citing works
Lin, X., Chen, D., Zhang, C., Zhang, X., Li, Z., Dong, B., Gao, J., & Shen, L. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0790-7 · Cited by 59 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Self-citationFumarate induces vesicular release of mtDNA to drive innate immunity
Zecchini, V. R., Paupe, V., Herranz-Montoya, I., Janssen, J. J. E., Wortel, I. M. N., Morris, J. L., Ferguson, A., Chowdhury, S. R., Segarra‐Mondejar, M., Costa, A. S. H., et al. (2023) · Nature · doi:10.1038/s41586-023-05770-w · Cited by 336 · see citing works
Self-citationThe functional roles of TCA cycle metabolites in cancer
Eniafe, J., & Jiang, S. (2021) · Oncogene · doi:10.1038/s41388-020-01639-8 · Cited by 274 · see citing works
Fumarate hydratase in cancer: A multifaceted tumour suppressor
Schmidt, C., Sciacovelli, M., & Frezza, C. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.002 · Cited by 163 · see citing works
Self-citationFumarate hydratase (FH) and cancer: a paradigm of oncometabolism
Valcárcel-Jiménez, L., & Frezza, C. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02412-w · Cited by 115 · see citing works
Self-citationInterplay between Cellular Metabolism and the DNA Damage Response in Cancer
Moretton, A., & Loizou, J. I. (2020) · Cancers · doi:10.3390/cancers12082051 · Cited by 93 · see citing works
TCA cycle signalling and the evolution of eukaryotes
Ryan, D. G., Frezza, C., & O'Neill, L. A. J. (2020) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2020.09.014 · Cited by 69 · see citing works
Self-citationGenomic instability and metabolism in cancer
Li, H., Zimmerman, S. E., & Weyemi, U. (2021) · International review of cytology · doi:10.1016/bs.ircmb.2021.05.004 · Cited by 64 · see citing works
Oncometabolites—A Link between Cancer Cells and Tumor Microenvironment
Baryła, M., Semeniuk-Wojtaś, A., Róg, L., Kraj, L., Małyszko, M., & Stec, R. (2022) · Biology · doi:10.3390/biology11020270 · Cited by 39 · see citing works
Johnson, T. I., Minteer, C. J., Kottmann, D., Dunlop, C. R., Fernández, S. B. D. Q., Carnevalli, L. S., Wallez, Y., Lau, A., Richards, F. M., & Jodrell, D. I. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103396 · Cited by 30 · see citing works
Self-citationOncometabolites and the response to radiotherapy
Xiang, K., Jendrossek, V., & Matschke, J. (2020) · Radiation Oncology · doi:10.1186/s13014-020-01638-9 · Cited by 29 · see citing works
Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways
Meng, W., Palmer, J. D., Siedow, M. R., Haque, S. J., & Chakravarti, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042246 · Cited by 30 · see citing works
Targeting Mitochondrial Oncometabolites: A New Approach to Overcome Drug Resistance in Cancer
Godel, M., Ortone, G., Anobile, D. P., Pasino, M., Randazzo, G., Riganti, C., & Kopecka, J. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13050762 · Cited by 23 · see citing works
Zhang, C., Li, L., Zhang, Y., & Zeng, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.686556 · Cited by 21 · see citing works
Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)
Lai, Y., Li, Z., Lu, Z., Zheng, H., Chen, C., Liu, C., Yang, Y., Tang, F., & He, Z. (2022) · Oncology Reports · doi:10.3892/or.2022.8428 · Cited by 17 · see citing works
Silas, Y., Singer, E., Das, K., Lehming, N., & Pines, O. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2026595118 · Cited by 18 · see citing works
Najera, S. S., Ricketts, C. J., Schmidt, L. S., Medina, J. I., Saito, K., Ileva, L. V., Brender, J., James, A. E., Peer, C. J., Gouker, B. A., et al. (2024) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-0225 · Cited by 14 · see citing works
Morilla, I., Chan, P., Caffin, F., Svilar, L., Selbonne, S., Ladaigue, S., Buard, V., Tarlet, G., Micheau, B., Paget, V., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103685 · Cited by 14 · see citing works
Mitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression
Jakoubě, P., Cutano, V., González-Morena, J. M., & Keckesova, Z. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0518 · Cited by 12 · see citing works
Vadhan, A., Yang, Y., Wang, Y., Chen, P., Tzou, S.-C., Cheng, K., Hu, S. C., Cheng, T., Wang, Y., & Yuan, S. F. (2022) · Oncology Letters · doi:10.3892/ol.2022.13627 · Cited by 12 · see citing works
Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells
Abad, E., Samino, S., Grodzicki, R. L., Pagano, G., Trifuoggi, M., Graifer, D., Potěšil, D., Zdráhal, Z., Yanes, Ó., & Lyakhovich, A. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.12.010 · Cited by 11 · see citing works
An Oncometabolite Isomer Rapidly Induces a Pathophysiological Protein Modification
Bergholtz, S. E., Briney, C. A., Najera, S. S., Perez, M., Linehan, W. M., & Meier, J. L. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00044 · Cited by 10 · see citing works
Álvarez-González, E., & Sierra, L. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25169054 · Cited by 10 · see citing works
Mitochondrial Factors in the Cell Nucleus
González‐Arzola, K., & Dı́az-Quintana, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713656 · Cited by 11 · see citing works
Pfefer, T., Bessenyei, A. H., & O'Neill, L. A. J. (2026) · Immunology Letters · doi:10.1016/j.imlet.2026.107153 · Cited by 8 · see citing works
Solaimuthu, B., Lichtenstein, M., Hayashi, A., Khatib, A., Plaschkes, I., Nevo, Y., Tanna, M., Pines, O., & Shaul, Y. D. (2022) · Cancers · doi:10.3390/cancers14225508 · Cited by 7 · see citing works
Oncometabolites as Regulators of DNA Damage Response and Repair
Gueble, S. E., & Bindra, R. S. (2021) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2021.09.004 · Cited by 8 · see citing works
Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy
Mostafavi, S., & Eskandari, N. (2023) · Cancer Reports · doi:10.1002/cnr2.1942 · Cited by 6 · see citing works
Uterine leiomyoma with fumarate hydratase deficiency
Huang, Y., Zhou, Y., Chen, X., Fang, Q., Cai, H., Xie, M., & Xing, Y. T. (2021) · Medicine · doi:10.1097/md.0000000000028142 · Cited by 5 · see citing works
Wei, G., Chen, J., Gong, X., & Zhang, D. (2024) · International Journal of Women s Health · doi:10.2147/ijwh.s444069 · Cited by 2 · see citing works
Meng, W., Xu, R. P., Miller, E. D., Sun, X., Thurmond, J. M., Webb, A., McElroy, J., Palmer, J. D., DiCostanzo, D. J., Zhang, S., et al. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.4c00529 · Cited by 2 · see citing works
Wang, R., & Yan, Z. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1671115 · Cited by 2 · see citing works
Large-scale analysis of chromosomal aberrations in uterine leiomyoma
Ilves, S., Jokinen, V., Katainen, R., Siili, E., Bützow, R. C., Heikinheimo, O., Pasanen, A. M., Karhu, A., Välimäki, N., & Aaltonen, L. A. (2026) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2026.01.010 · Cited by 2 · see citing works
Depletion of FH, an essential TCA cycle enzyme, drives proliferation in a two-step modelPreprint
Solaimuthu, B., Lichtenstein, M., Hayashi, A., Khatib, A., Plaschkes, I., Nevo, Y., Tanna, M., Lavi, S., Pines, O., & Shaul, Y. D. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.16.496410 · Cited by 2 · see citing works
Silas, Y., Singer, E., Das, K., Lehming, N., & Pines, O. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.04.232652
Oncometabolites, epigenetic marks, and DNA repair
Dow, J., & Glazer, P. M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91081-1.00008-x
Zuo, M., Fu, J., & Liao, G. (2025) · Aging Research · doi:10.26599/agr.2025.9340053
Liu, W., Jiang, X., Ma, Y., Qing, H., Bao, Y., & Jiao, Z. (2025) · Medical Oncology · doi:10.1007/s12032-025-03053-0
Liu, N., Shen, C., Zhou, T., Zhou, Y., Yuan, H., Bi, H., Wang, Y., Pei, X., Su, R. J., Trisal, V., et al. (2026) · Cancer & Metabolism · doi:10.1186/s40170-026-00435-4 · Cited by 1 · see citing works
- Authors
- Johnson, T. I., Costa, A. S. H., Ferguson, A. N., & Frezza, C.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Frezza, Christian
- Venue
- Cell Death & Disease
- Published
- 2018-09-06
- Volume
- 9
- Issue
- 9
- Pages
- 913-913
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6127199
- OpenAlex
- W2890126224
- Cited by
- 40
- References
- 22
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 1 · 2018: 1
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Medical Research Council (MC_UU_12022/6, SKAG106)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- fumarate hydratase, fumarate accumulation, ionizing radiation, DNA damage response, G2 checkpoint, mitotic entry, non-homologous end joining, homologous recombination, DNA double-strand breaks, genomic instability, hereditary leiomyomatosis and renal cell carcinoma, DNA damage foci, radioresistance (biology)
- MeSH terms
- Carcinoma, Renal Cell, DNA Damage, DNA Repair, Fumarate Hydratase, Humans, Kidney Neoplasms, Mitosis, Neoplastic Syndromes, Hereditary, Radiation, Ionizing, Skin Neoplasms, Uterine Neoplasms, G2 Phase, Germ-Line Mutation, Leiomyomatosis, Genomic Instability, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
