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。
IDH1R132H Mutant Glioma and Its Compensatory Mechanisms for Maintaining Telomeres
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 IDH1R132H 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 IDH1R132H 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 IDH1R132H 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 for the HR pathway to promote ALT.Finally,the IDH1R132H has a decreased affinity for isocitric acid and NADP+and an increased affinity for α ketoglutarate(α-KG)and NADPH,so that the mutant IDH1R132H catalyzes the hydrogenation of α-KG to produce 2-hydroxyglutarate(2-HG)in a NADPH-dependent manner.Because 2-HG is structurally similar to α-KG,which maintains the trimethylation level of H3k9me3 by competitively inhibiting the activity of the α-KG-dependent histone demethylase KDM4B,and recruits heterochromatin protein HP1α to heterochromatinize telomeres,and promote ALT phenotypes in cooperation with the inactivating of ATRX.In addition,it has been shown that APBs contain telomeric chromatin,which is essentially heterochromatin,and HP1α is directly involved in the formation of APBs.Based on these studies,this article reviews the mechanism of IDH1R132H mediated telomere dysfunction and the preference of DNA repair pathway at telomeres in cooperate with ATRX loss to promote ALT,which may provide references for clinical targeted therapy of IDH1R132H mutant glioma.
gliomaIDH1R132Halterative lengthening of telomere(ALT)
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