ATRX modulates the escape from a telomere crisis.
ATRX modulates the escape from a telomere crisis.
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DOI：
10.1371/journal.pgen.1010485
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发表时间：
2022-11
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
端粒酶活性是人类癌症中主要的端粒维持机制，然而，15%的癌症利用基于重组的机制，称为端粒的交替延长（ALT），其导致长且异质的端粒长度分布。α地中海贫血/智力迟钝综合征X连锁（ATRX）基因的功能丧失突变经常在ALT癌症中发现。在这里，我们证明，ATRX的损失，再加上端粒功能障碍，在危机期间，足以启动激活ALT途径，它赋予人类成纤维细胞的复制永生。此外，ATRX的丧失与HCT 116上皮癌细胞中端粒驱动的危机相结合，导致ALT样途径的启动。在这些细胞中，观察到快速和精确的端粒延长和C环的诱导;然而，这个过程是短暂的，端粒最终继续侵蚀，使得细胞死亡或从危机中逃脱与端粒酶激活相关。在这两种情况下，端粒测序显示，所有的等位基因，无论他们是否延长，都富含变异重复类型，这似乎是细胞系特异性的。因此，我们的数据表明，ATRX的损失结合端粒功能障碍在危机期间诱导成纤维细胞中的ALT途径，并使ALT在上皮细胞中的短暂激活。端粒是一种核蛋白结构，覆盖在线性染色体的末端，对染色体的稳定性至关重要，但随着细胞分裂的进行而逐渐缩短。端粒DNA的缺失最终导致末端加帽功能的丧失，诱导广泛的基因组不稳定和细胞危机。这段危机时期导致获得端粒维持机制（TMM），这是赋予癌细胞复制永生所必需的。大多数肿瘤类型使用端粒酶作为它们的TMM，但一个重要的癌症子集利用端粒（ALT）途径的替代延长。在这里，我们表明，在α地中海贫血/智力迟钝综合征X连锁（ATRX）基因的情况下，成纤维细胞，很少逃脱危机，可以有效地逃避危机诱导ALT途径。相反，具有活化的端粒酶的逃避危机的上皮细胞受到ATRX不存在的限制，但可以在小比例的细胞中诱导瞬时ALT样活性。我们的数据表明，ATRX在间充质来源的细胞中端粒驱动的危机期间赋予端粒稳定性和限制克隆进化方面具有重要作用。
Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells. Telomeres are nucleoprotein structures that cap the ends of linear chromosomes, they are essential for chromosomal stability, but gradually shorten with ongoing cell division. The loss of telomeric DNA ultimately leads to the loss of the end capping function, the induction of widespread genomic instability and cellular crisis. This period of crisis leads to the acquisition of telomere maintenance mechanisms (TMM) that are required to confer replicative immortality in cancer cells. The majority of tumour types use telomerase as their TMM, but a significant subset of cancers utilise the alternative lengthening of telomeres (ALT) pathway. Here we show that, in the absence of the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene, fibroblast cells, that very rarely escape crisis, can efficiently escape crisis having induced the ALT pathway. In contrast, epithelial cells that escape crisis having activated telomerase, are restricted by the absence of ATRX, but can induce a transient ALT-like activity in a small proportion of cells. Our data point to an important role of ATRX in conferring telomere stability and restricting clonal evolution during a telomere-driven crisis in cells of a mesenchymal origin.
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影响因子：
64.5
作者：
Goldberg AD;Banaszynski LA;Noh KM;Lewis PW;Elsaesser SJ;Stadler S;Dewell S;Law M;Guo X;Li X;Wen D;Chapgier A;DeKelver RC;Miller JC;Lee YL;Boydston EA;Holmes MC;Gregory PD;Greally JM;Rafii S;Yang C;Scambler PJ;Garrick D;Gibbons RJ;Higgs DR;Cristea IM;Urnov FD;Zheng D;Allis CD
通讯作者：
Allis CD
通过诱导端粒 DNA 损伤以及 ATRX 和 DAXX 功能障碍，将端粒酶切换为 ALT 机制
影响因子：
4.6
作者：
Hu Y;Shi G;Zhang L;Li F;Jiang Y;Jiang S;Ma W;Zhao Y;Songyang Z;Huang J
通讯作者：
Huang J
影响因子：
4.4
作者：
Abid, Heba Z.;McCaffrey, Jennifer;Xiao, Ming
通讯作者：
Xiao, Ming
影响因子：
11.4
作者：
BRYAN, TM;ENGLEZOU, A;REDDEL, RR
通讯作者：
REDDEL, RR
影响因子：
9.8
作者：
Baird, DM;Coleman, J;Royle, NJ
通讯作者：
Royle, NJ