Oncometabolites suppress DNA repair by disrupting local chromatin signalling.
|核心内容：
新陈代谢的失调和基因组完整性的破坏是癌症的标志。
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水合酶(FH)和琥珀酸脱氢酶基因(SDHA、SDHB、SDHC和SDHD)的种系突变，人类恶性肿瘤中代谢产物2-羟基戊二酸、琥珀酸和富马酸水平分别升高。
最近的工作在这些代谢物和DNA修复之间建立了一个意想不到的联系，表明它们抑制了同源依赖修复(HDR)的途径，并赋予了对临床试验中正在测试的聚(ADP-核糖)聚合酶(PARP)抑制剂的极高敏感性。
然而，这些肿瘤代谢物抑制HDR的机制仍然知之甚少。
在这里，我们确定了这些代谢物破坏DNA修复的途径。
我们发现，肿瘤性代谢物诱导的赖氨酸脱甲基酶KDM4B的抑制导致组蛋白3赖氨酸9(H3K9)在DNA断裂周围的位点异常高甲基化，掩盖了对HDR的正确执行至关重要的局部H3K9三甲基化信号。
因此，近端HDR的两个关键因子Tip60和ATM的募集在DNA断裂时显著受损，末端切除减少，下游修复因子的募集减少。
这些发现为肿瘤代谢物诱导的HDR抑制提供了机制基础，并可能指导有效的策略来利用这些缺陷来获得治疗收益。
hyperH3K9me3~Tip60和ATM募集、末端切除、下游修复因子的募集都减少。赖氨酸脱甲基酶KDM4B的活性可以维持合理的H3K9me3，介导正常的HDR;
原文摘要：
Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer.
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), respectively.
FH germline mutations~fumarate ;
SDHA, SDHB, SDHC and SDHD germline mutations~succinate ;
IDH1 or IDH2 germline mutations~fumarate ,succinate accumulation；
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) 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.
参考文献：10.1038/s41586-020-2363-0
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