A new path to alternative lengthening of telomeres?
A new path to alternative lengthening of telomeres?
复制标题
端粒替代延长的新途径？
DOI：
10.1093/neuonc/noad054
复制
发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Becher,OrenJ
中科院分区：
文献类型：
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作者：
Becher,OrenJ
端粒是位于染色体末端的DNA-蛋白质复合物，其屏蔽染色体末端，并且其缩短是衰老的标志。1人类端粒由共有5 '-TTAGGG-3'重复的长串联重复序列阵列组成，其间散布着序列变异重复序列。端粒在每次细胞分裂过程中缩短，如果没有端粒维持机制，复制性衰老就会加剧。端粒的主要作用是防止线性染色体的末端被识别为DNA双链断裂。2在癌症的背景下，细胞最常见的是通过上调端粒酶来维持其复制潜力，端粒酶是一种核糖核蛋白复合物，可以使用其RNA模板将5 '-TTAGGG-3'重复序列添加到端粒中。第二种机制称为端粒交替延长（ALT），是一种基于重组的端粒维持机制，它不依赖于端粒酶。3ALT主要见于间质或神经上皮来源的癌症。一般而言，在神经胶质肿瘤中，用于维持端粒长度的2种主要机制是端粒酶逆转录酶（TERT）的启动子突变和ALT，其与染色质重塑因子α地中海贫血精神发育迟滞X连锁蛋白或ATRX突变最相关。儿科高级别胶质瘤（pHGG）通常在H3中携带癌组蛋白突变（最常见的是H3 K27 M和H3 G34 R），很少携带TERT启动子突变，约30%携带与ALT强相关的ATRX突变。4
Telomeres are DNA-protein complexes located at the end of chromosomes that shield chromosome ends and their shortening is a hallmark of aging. 1 Human telomeres comprise of long tandem repeats arrays of the consensus 5’-TTAGGG-3’repeat, interspersed with sequence-variant repeats. Telomeres shorten during each cellular division, and without telomere maintenance mechanisms, replicative senescence ensues. The primary role of telomeres is to prevent the ends of linear chromosomes from being recognized as DNA double-strand breaks. 2 In the context of cancer, cells most commonly maintain their replicative potential through upregulation of telomerase, a ribonucleoprotein complex that can add 5'-TTAGGG-3'repeats to telomeres using its RNA template. A second mechanism, termed alternative lengthening of telomeres (ALT), is a recombination-based telomere maintenance mechanism which is telomerase independent. 3ALT is primarily observed in cancers of mesenchymal or neuroepithelial origin. In glial tumors in general, the 2 primary mechanisms used to maintain telomere length are promoter mutations in Telomerase reverse transcriptase (TERT), and ALT, most associated with the chromatin remodeler alphathalassemia mental retardation X-linked protein or ATRX mutations. Pediatric high-grade gliomas (pHGG), which commonly harbor onco-histone mutations in H3 (most commonly H3K27M and H3G34R), rarely harbor TERT promoter mutations with approximately 30% harboring ATRX mutations with strong correlation with ALT. 4