Couteau Florence, Gagné Laurence M, Boulay Karine, Rousseau Philippe, Carbonneau Mélissa, McQuaid Mary, Sharma Jyoti, Sawchyn Christina, Fernandez Erlinda, Glatz Dagmar, Rizk Rana, Lalonde Marie-Eve, Mehrjoo Yosra, Chu Tsz Wai, Moquin-Beaudry Gaël, Beauséjour Christian, Sergeev Mikhail, Costantino Santiago, Avizonis Daina, Topisirovic Ivan, Jabado Nada, Wurtele Hugo, Autexier Chantal, Mallette Frédérick A
Maisonneuve-Rosemont Hospital Research Centre, Montréal, Qc, H1T 2M4, Canada.
Département de Biochimie et Médecine Moléculaire, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Qc, H3C 3J7, Canada.
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf512.
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.
编码细胞代谢因子的基因发生突变、缺失或沉默在人类恶性肿瘤中频繁出现。异柠檬酸脱氢酶1和2（IDH1/2）的新形态突变促进了R-2-羟基戊二酸（R-2HG）而非α-酮戊二酸（αKG）的产生，这种突变在人类脑癌中反复出现，并且是低级别胶质瘤发生过程中的早期事件。由于R-2HG与αKG结构相似，它可作为αKG依赖性酶的抑制剂。这些酶包括JUMONJI家族的赖氨酸去甲基化酶，其中KDM4A对R-2HG介导的抑制特别敏感。然而，R-2HG抑制αKG依赖性酶促进胶质瘤发生的确切分子机制仍知之甚少。在此，我们表明用R-2HG处理以p53依赖性方式诱导细胞衰老。此外，突变型IDH1R132H的表达或暴露于导致KDM4A抑制的R-2HG会导致端粒功能障碍。我们证明KDM4A定位于端粒重复序列并调节端粒处H3K9（me3）的丰度。我们表明R-2HG导致复制叉进展减慢，并且参与复制叉逆转的解旋酶SMARCAL1的缺失挽救了由R-2HG或KDM4A缺失引起的端粒缺陷。这些结果建立了一个模型，即IDH1/2突变导致R-2HG介导的KDM4A抑制，导致端粒DNA复制缺陷、端粒功能障碍和相关的基因组不稳定。
