<i>R</i>-2-hydroxyglutarate-mediated inhibition of KDM4A compromises telomere integrity
Mutation, deletion, or silencing of genes encoding cellular metabolism factors occurs frequently in human malignancies. Neomorphic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) promoting the production of R-2-hydroxyglutarate (R-2HG) instead of α-ketoglutarate (αKG) are recurrent in human brain cancers and constitute an early event in low-grade gliomagenesis. Due to its structural similarity with αKG, R-2HG acts as an inhibitor of αKG-dependent enzymes. These include the JUMONJI family of lysine demethylases, among which KDM4A is particularly sensitive to R-2HG-mediated inhibition. However, the precise molecular mechanism through which inhibition of αKG-dependent enzymes by R-2HG promotes gliomagenesis remains poorly understood. Here, we show that treatment with R-2HG induces cellular senescence in a p53-dependent manner. Furthermore, expression of mutated IDH1R132H or exposure to R-2HG, which leads to KDM4A inhibition, causes telomeric dysfunction. We demonstrate that KDM4A localizes to telomeric repeats and regulates abundance of H3K9(me3) at telomeres. We show that R-2HG caused reduced replication fork progression, and that depletion of SMARCAL1, a helicase involved in replication fork reversal, rescues telomeric defects caused by R-2HG or KDM4A depletion. These results establish a model whereby IDH1/2 mutations cause R-2HG-mediated inhibition of KDM4A, leading to telomeric DNA replication defects, telomere dysfunction, and associated genomic instability.
Authors
- Ivan Topisirović
- Tsz Wai Chu
- Gaël Moquin‐Beaudry (ORCID: https://orcid.org/0000-0003-3286-3188)
- Chantal Autexier (ORCID: https://orcid.org/0000-0002-7201-0975)
- Santiago Costantino (ORCID: https://orcid.org/0000-0002-2454-2635)
- Philippe Rousseau (ORCID: https://orcid.org/0000-0002-6376-6527)
- Hugo Würtele (ORCID: https://orcid.org/0000-0002-5733-1711)
- Karine Boulay (ORCID: https://orcid.org/0000-0002-8991-3388)
- Christian Beauséjour (ORCID: https://orcid.org/0000-0002-1693-5172)
- Jyoti Sharma (ORCID: https://orcid.org/0000-0003-3299-9907)
- Laurence M. Gagné
- Mélissa Carbonneau
- Daina Zofija Avizonis (ORCID: https://orcid.org/0000-0002-3843-255X)
- Mikhail Sergeev (ORCID: https://orcid.org/0000-0001-7047-2378)
- Mary McQuaid (ORCID: https://orcid.org/0000-0002-0491-127X)
- Dagmar Glatz
- Nada Jabado (ORCID: https://orcid.org/0000-0003-2485-3692)
- Florence Couteau
- Christina Sawchyn (ORCID: https://orcid.org/0000-0002-0413-3762)
- Rana Rizk (ORCID: https://orcid.org/0000-0002-8850-6502)
- Frédérick A. Mallette (ORCID: https://orcid.org/0000-0001-7932-0338)
- Yosra Mehrjoo (ORCID: https://orcid.org/0009-0007-0807-7378)
- Erlinda Fernández (ORCID: https://orcid.org/0000-0002-3630-7587)
- Marie‐Eve Lalonde
Institutions
- McGill University Health Centre (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Hôpital Maisonneuve-Rosemont (CA)
- Occupational Cancer Research Centre (CA)
- McGill University (CA)
- Université de Montréal (CA)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1093/nar/gkaf512
- Citations
- 4
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- Chesapeake Research Consortium
- McGill University
- Cancer Research Society
- Fondation de l’Hôpital Maisonneuve-Rosemont
- Cole Foundation
- Canada Foundation for Innovation
- Terry Fox Foundation
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé