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Contributions of IDH1 mutation to alternative lengthening of telomeres in lower-grade glioma

IDH1 突变对低级别胶质瘤端粒选择性延长的贡献

基本信息

批准号：
10171926
负责人：
Russell O. Pieper
金额：
$ 34.67万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171926
关键词：
ATRX gene Abnormal Cell Astrocytes Astrocytoma Automobile Driving Base Excision Repairs Cell Cycle Cell Death Cells Characteristics Chromosomes Complex DNA DNA Repair Dioxygenases Dissociation Down-Regulation Functional disorder Gene Expression Generations Genetic Genetic Suppression Glioma Gliomagenesis Human In Vitro Isocitrate Dehydrogenase Link Malignant Glioma Modeling Mutation Neuroglia Nonhomologous DNA End Joining Pathway interactions Pattern Pharmacology Phenotype Proteins Regulation Resolution Retinoblastoma Protein Sister Chromatid Exchange System TP53 gene Telomerase Telomere Capping Telomere Shortening Testing Therapeutic Time Work XRCC1 gene Xenograft procedure alpha ketoglutarate base cell growth chromatin remodeling chromosome fusion histone methylation homologous recombination improved in vivo loss of function mutation mutant overexpression repaired telomere therapeutic target tumorigenesis tumorigenic virtual

项目摘要

The long term objective of this proposal is to improve the therapy of lower-grade astrocytoma (LGA) by glioma by defining how expression of the mutant IDH1 protein contributes to alternative lengthening of telomeres (ALT). LGA account for 20% of all malignant glioma, and nearly all progress over time to fatal high-grade glioma. Most LGA express a mutant form of isocitrate dehydrogenase (IDH1mut) that generates the oncometabolite 2-hydroxyglutarate, alters gene expression, and drives tumorigenesis. An unexplored aspect of how IDH1mut drives gliomagenesis is its potential link to telomere regulation. Telomeres are DNA repeats at the ends of chromosomes that, in the absence of TERT, shorten with each cell cycle, eventually leading to dissociation of a telomere-protective sheltrin cap, chromosomal fusion, and cell death. Telomeric dysfunction is resolved in most glioma cells by TERT reactivation. Virtually all LGA, however, use an alternative, homologous recombination (HR)-based mechanism to elongate telomeres and survive in the absence of TERT. We recently showed that expression of IDH1mut in an ATRX-deficient background was sufficient to drive the ALT phenotype in p53/pRb- deficient human astrocytes. These ALT cells, as well as IDH1mut LGA, consistently downregulated RAP1 and XRCC1, and re-expression of XRCC1 and/or RAP1 suppressed the ALT phenotype. RAP1 is part of the sheltrin complex, and its loss can cause telomere uncapping. XRCC1 in turn is a critical component of the alternative non-homologous end joining (aNHEJ) pathway that generates lethal chromosome end-to-end fusions following telomere uncapping. Based on these observations we hypothesize that IDH1mut-driven down- regulation of RAP1 and XRCC1 leads to telomere dysfunction and inhibition of the aNHEJ pathway, enabling IDH1mut /ATRX-deficient cells to use HR and ALT to resolve telomeric dysfunction and escape cell death. This hypothesis will be tested by determining 1) if downregulation of RAP1 causes telomeric dysfunction, and if this contributes to IDH1mut- driven ALT, 2) if downregulation of XRCC1 changes the pathway by which uncapped telomeres are repaired, and if this contributes to IDH1mut- driven ALT, and 3) if IDH1mut-driven changes in DNA repair provide collateral therapeutic vulnerability.

该提案的长期目标是改善低级别星形细胞瘤的治疗 (LGA) 通过定义突变 IDH1 蛋白的表达如何有助于神经胶质瘤端粒的选择性延长（ALT）。 LGA 占所有恶性神经胶质瘤的 20%，随着时间的推移，几乎所有疾病都会进展为致命的高级神经胶质瘤。大多数 LGA 表达突变形式异柠檬酸脱氢酶 (IDH1mut) 产生致癌代谢物 2-羟基戊二酸，改变基因表达，并驱动肿瘤发生。 IDH1mut 驱动方式的一个未被探索的方面神经胶质瘤发生是其与端粒调节的潜在联系。端粒是 DNA 的重复序列染色体末端在没有 TERT 的情况下会随着每个细胞周期而缩短，最终导致端粒保护性谢特蛋白帽解离、染色体融合和细胞死亡。大多数神经胶质瘤细胞的端粒功能障碍可通过 TERT 重新激活得到解决。几乎所有然而，LGA 使用另一种基于同源重组 (HR) 的机制来延长端粒并在没有 TERT 的情况下存活。我们最近展示了这个表达式 ATRX 缺陷背景中的 IDH1mut 足以驱动 p53/pRb- 中的 ALT 表型人类星形胶质细胞缺陷。这些 ALT 细胞以及 IDH1mut LGA 一致下调 RAP1 和 XRCC1，XRCC1 和/或 RAP1 的重新表达抑制 ALT 表型。 RAP1是sheltrin复合物的一部分，它的丢失会导致端粒开盖。 XRCC1 又是替代非同源末端的关键组成部分连接（aNHEJ）途径，产生致命的染色体端到端融合端粒脱帽。基于这些观察，我们假设 IDH1mut 驱动的下调 RAP1 和 XRCC1 的调节导致端粒功能障碍和 aNHEJ 抑制途径，使 IDH1mut /ATRX 缺陷细胞能够利用 HR 和 ALT 来解析端粒功能障碍和逃避细胞死亡。该假设将通过确定 1) 是否 RAP1 的下调会导致端粒功能障碍，如果这有助于 IDH1mut 驱动 ALT, 2) 如果 XRCC1 的下调改变了未加帽端粒的通路修复，并且这是否有助于 IDH1mut 驱动的 ALT，以及 3) 如果 IDH1mut 驱动的 DNA 变化修复提供了附带的治疗脆弱性。