异柠檬酸脱氢酶IDH1突变影响细胞与组织中DNA损伤修复相关分子机制

IDH1 and IDH2 represent by far the most frequently mutated metabolic genes in human cancers. Tumor-derived IDH1/2 mutations result in simultaneous loss of its normal activity in producing α-ketoglutarate (α-KG, also known as 2-oxyglutarate) and gain of a new activity in catalyzing the reduction of α-KG to produce 2-hydroxyglutarate (2-HG).2-HG is structurally similar to α-KG and acts as a competitive antagonist of α-KG, thus its accumulation in tumor cells can lead to the inhibition of multiple α-KG-dependent dioxygenases, including the JmjC domain-containing histone demethylases (KDMs) and the TET (ten-eleven translocation) family of DNA hydroxylases.Alteration of epigenetic control through impairing both histone and DNA methylation as a mechanism of promoting tumorigenesis by IDH mutation has received strong biochemical and genetic supports.Recent studies have found clear benefits of chemotherapy with alkylators in patients with IDH-mutated tumors. In the study, we will take more insights into the IDH biology, investigating the underlying mechanisms by which IDH1 mutation affects DNA repair pathways and its contribution to tumorigenesis. Our study will provide scientific basis to refine chemotherapy regimen for IDH mutant containing cancer treatment.

异柠檬酸脱氢酶基因IDH1 和IDH2 是在肿瘤中发生突变频率最高的代谢基因，但人们至今还没有从机制上完全阐明IDH 突变如何诱导肿瘤发生。我们前期研究表明，IDH1/2 突变导致的代谢失衡会影响α-KG 依赖型组蛋白和DNA 去甲基化酶的活力，改变组蛋白和DNA 甲基化水平，调控下游基因转录，从而可能影响干细胞或前体细胞的分化，最终促进肿瘤发生。鉴于临床上已报道的"IDH1/2 突变肿瘤患者对DNA 损伤剂具较高敏感性"这一现象，本项目将深入研究IDH1 突变如何影响DNA 损伤修复相关基因转录活性以及在DNA 损伤修复过程中起关键作用的α-KG 依赖型AlkB 蛋白功能，揭示IDH1 突变通过影响细胞和组织中DNA 损伤修复，促进肿瘤发生的分子调控网络。本项目的实施和完成将拓展人们对IDH突变诱发肿瘤分子机制的科学认知，也将有助于提高IDH1突变肿瘤个体化治疗的有效性,避免盲目治疗。

异柠檬酸脱氢酶基因 IDH1 和 IDH2 是最常见的在肿瘤中发生突变的代谢基因。最近的临床数据表明， IDH突变脑胶质瘤患者对联合使用烷基化试剂甲基苄肼（Procabazine）、环己亚硝脲（Lomustine，别名CCNU）和微管药物长春新碱（Vincristine）的化疗方法（简称PCV化疗）特别敏感。本项目结合 IDH1/2 突变的生化及临床病理特征，深入研究 IDH1 突变如何影响 DNA 损伤修复相关基因转录活性以及在 DNA 损伤修复过程中起关键作用的α-KG 依赖型 AlkB 蛋白功能，揭示 IDH1 突变通过影响细胞和组织中DNA 损伤修复，促进肿瘤发生的分子调控网络。