异柠檬酸脱氢酶1 R132H突变型胶质细胞瘤及其维持端粒的代偿机制  

IDH1R132H Mutant Glioma and Its Compensatory Mechanisms for Maintaining Telomeres

作　　者：闫思翔 李逸凡 李瑶 李奕璇 李香秀 仝津恺 贾舒婷[1] 旦菊花 YAN Si-Xiang;LI Yi-Fan;LI Yao;LI Yi-Xuan;LI Xiang-Xiu;TONG Jin-Kai;JIA Shu-Ting;DAN Ju-Hua(Laboratory of Molecular Genetics of Aging and Tumor,Medical School,Kunming University of Science and Technology,Kunming 650500,China)

机构地区：[1]昆明理工大学基础医学院,衰老与肿瘤分子遗传学实验室,昆明650500

出　　处：《生物化学与生物物理进展》2024年第11期2845-2852,共8页Progress In Biochemistry and Biophysics

基　　金：昆明理工大学课外学术科技创新基金(2022ZK109);昆明理工大学与云南省第一人民医院联合资助自然科学基金(KUSTKH2022009Y)资助项目。

摘　　要：异柠檬酸脱氢酶1 (isocitrate dehydrogenase 1,IDH1) R132H是Ⅱ-Ⅲ级胶质瘤和少突胶质细胞瘤中最常见的突变基因。绝大多数IDH1R132H突变型胶质细胞瘤并没有通过端粒酶的激活(在端粒酶逆转录酶TERT的介导下以RNA为模板延伸端粒长度)作为其端粒维持机制,而是通过一种依赖于同源重组(homologous recombination,HR)的代偿机制来维持端粒长度,该机制被称为端粒延长替代(alterative lengthening of telomere,ALT),目前关于ALT形成的机制尚不完全清楚。最近的研究表明,端粒Shelterin复合物组分RAP1和非同源DNA末端连接(non-homologous end joining,NHEJ)修复因子XRCC1的表达在IDH1R132H突变的胶质细胞瘤中均一致下调,导致端粒功能障碍并促进HR。同时,IDH1R132H突变通过下调去甲基化酶KDM4B的活性水平,与α地中海贫血伴智力低下综合征X连锁(alpha thalassemia/mental retardation syndrome X-linked,ATRX)基因缺失协同作用促进ALT途径。基于这些研究,本文就突变IDH1R132H的表达如何引发端粒功能障碍并改变端粒处的DNA修复途径偏好,进而与ATRX丢失协同作用促进ALT发生的机制进行综述。为临床靶向治疗IDH1R132H突变型胶质细胞瘤提供参考。Isocitrate dehydrogenase 1(IDH1)R132H is the most common mutated gene in grade Ⅱ-Ⅲ gliomas and oligodendrogliomas.Instead of activating telomerase(a reverse transcriptase which using RNA as a template to extend telomere length),the majority of IDH1^(R132H) mutant glioma maintain telomere length through an alternative mechanism that relies on homologous recombination(HR),which is known as alterative lengthening of telomere(ALT).The phenotype of ALT mechanism include:ALT associated promyelocytic leukemia protein(PML)bodies(APBs);extrachromosomal telomeric DNA repeats such as C-and T-loops;telomeric sister chromatid exchange(T-SCE),etc.The mechanism of ALT activation is not fully understood.Recent studies have shown that mutation IDH1 contributes to ALT phenotype in glioma cells in at least three key ways.Firstly,the IDH1^(R132H) mutation mediates RAP1 down-regulation leading to telomere dysfunction,thus ensuring persistent endogenous telomeric DNA damage,which is important for ALT activation.Spontaneous DNA damage at telomeres may provide a substrate for mutation break-induced replication(BIR)‑mediated ALT telomere lengthening,and it has been demonstrated that RAP1 inhibits telomeric repeat-containing RNA,transcribed from telomeric DNA repeat sequences(TERRA)transcription to down-regulate ALT telomere DNA replication stress and telomeric DNA damage,thereby inhibiting ALT telomere synthesis.Similarly,in ALT cells,knockdown of telomere-specific RNaseH1 nuclease triggers TERRA accumulation,which leads to increased replication pressure.Overexpression of RNaseH1,on the other hand,attenuates the recombination capacity of ALT telomeres,leading to telomere depletion,suggesting that RAP1 can regulate the level of replication pressure and thus ALT activity by controlling TERRA expression.Secondly,the IDH1^(R132H) also alters the preference of the telomere damage repair pathway by down-regulating XRCC1,which inhibits the alternative non-homologous end joining(A-NHEJ)pathway at telomeres and alters cellular preference fo

关 键 词：胶质瘤 异柠檬酸脱氢酶1 R132H 端粒延长替代 

分 类 号：Q71[生物学—分子生物学]