Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
The Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen, Bergen, Norway.
Cancer Res. 2018 Jun 1;78(11):2966-2977. doi: 10.1158/0008-5472.CAN-17-2269. Epub 2018 Mar 15.
A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis. Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. .
肿瘤的亚群利用基于重组的端粒（ALT）途径来解决端粒功能障碍，而无需 TERT。染色质重塑因子 ATRX 的功能丧失突变与 ALT 相关，但不足以驱动该过程。由于许多 ALT 肿瘤表达突变的异柠檬酸脱氢酶 IDH1 R132H，包括所有低级别星形细胞瘤和继发性胶质母细胞瘤，因此我们研究了 IDH1 R132H 在胶质母细胞瘤发生过程中驱动 ALT 表型的假设作用。在 p53/pRb 缺陷型人星形细胞瘤中，ATRX 的联合缺失和突变 IDH1 的表达足以创建具有 ALT 特征的肿瘤细胞。端粒加帽复合物成分 RAP1 和非同源 DNA 末端连接修复因子 XRCC1 在这些肿瘤细胞中均持续下调，其协调表达足以抑制 ALT 表型。RAP1 或 XRCC1 的下调与 ATRX 缺失共同驱动 ALT 表型。RAP1 沉默导致 ATRX 缺陷细胞中端粒功能障碍，而 XRCC1 沉默通过允许 IDH1 突变 ATRX 缺陷细胞利用同源重组和 ALT 来解决端粒功能障碍并逃避细胞死亡，从而抑制了功能失调端粒的致命融合。总体而言，我们的研究表明突变 IDH1 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，与 ATRX 缺失合作，克服胶质母细胞瘤发生的关键障碍。研究表明突变 IDH1 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，与 ATRX 缺失合作，克服胶质母细胞瘤发生的关键障碍，并为治疗低级别胶质瘤提供新的治疗选择。
