美国耶鲁大学医学院Peter M. Glazer和Ranjit S. Bindra团队合作取得新进展。他们揭示肿瘤代谢物通过破坏局部染色质信号传导抑制DNA修复。2020年6月3日，《自然》发表了这一成果。

他们确定了这些代谢物破坏DNA修复的途径。研究显示肿瘤代谢物诱导的赖氨酸去甲基化酶KDM4B抑制，导致组蛋白3赖氨酸9（H3K9）在围绕DNA断裂的基因座处异常高甲基化，掩盖了局部H3K9三甲基化信号，这个信号对于正确执行同源依赖性修复（HDR）是必不可少的。因此，在DNA断裂时，两个关键的近端HDR因子TIP60和ATM的募集被大大受损，末端切除减少，下游修复因子的募集减少。

这些发现提供了竞争性肿瘤代谢物诱导的HDR抑制的机制基础，并可能指导有效的策略来利用这些缺陷使治疗获益。

据悉，代谢失调和基因组完整性破坏是癌症的标志。由于异柠檬酸脱氢酶-1或-2（IDH1或IDH2）基因的体细胞突变，或富马酸盐水合酶（FH）和琥珀酸脱氢酶基因（SDHA，SDHB，SDHC和SDHD）的种系突变，分别导致人类恶性肿瘤中2-羟基戊二酸、琥珀酸和富马酸代谢物的含量增加。

最近的工作表明这些代谢产物抑制HDR的途径，并赋予其对聚（ADP-核糖）聚合酶（PARP）抑制剂极强的敏感性，从而在这些代谢产物与DNA修复之间建立了意想不到的联系。然而，这些代谢产物抑制HDR的机制仍知之甚少。

附：英文原文

Title: Oncometabolites suppress DNA repair by disrupting local chromatin signalling

Author: Parker L. Sulkowski, Sebastian Oeck, Jonathan Dow, Nicholas G. Economos, Lily Mirfakhraie, Yanfeng Liu, Katelyn Noronha, Xun Bao, Jing Li, Brian M. Shuch, Megan C. King, Ranjit S. Bindra, Peter M. Glazer

Issue&Volume: 2020-06-03

Abstract: Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer1. Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively2,3,4. Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)5,6 and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.

DOI: 10.1038/s41586-020-2363-0

Source: https://www.nature.com/articles/s41586-020-2363-0