Suppr超能文献

端粒3'端悬突缩短与霍耶拉尔-赫雷戴松综合征中的端粒功能障碍有关。

Diminished telomeric 3' overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome.

作者信息

Lamm Noa, Ordan Elly, Shponkin Rotem, Richler Carmelit, Aker Memet, Tzfati Yehuda

机构信息

Department of Genetics, The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel.

出版信息

PLoS One. 2009 May 22;4(5):e5666. doi: 10.1371/journal.pone.0005666.

Abstract

BACKGROUND

Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency.

METHODOLOGY/PRINCIPAL FINDINGS: We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3' overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types.

CONCLUSIONS/SIGNIFICANCE: Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.

摘要

背景

真核生物染色体末端是端粒,在大多数生物体中,端粒由与端粒蛋白相关的串联DNA重复序列组成。这些DNA重复序列由端粒酶合成,端粒酶在大多数人体组织中的活性受到严格调控,导致端粒随着细胞分裂逐渐缩短。缩短超过临界长度会导致端粒解帽,表现为DNA损伤反应(DDR)激活,进而导致细胞周期停滞。因此,端粒长度限制了细胞分裂次数,并提供了一种肿瘤抑制机制。然而,不仅端粒缩短,而且受损的端粒结构也会导致端粒解帽。先天性角化不良(DC)及其严重形式霍耶拉尔 - 赫雷达尔松综合征(HHS)是主要由端粒酶缺乏、端粒加速缩短、细胞增殖受损、骨髓衰竭和免疫缺陷所特征的遗传性疾病。

方法/主要发现:我们研究了一个受HHS影响的家族中的端粒表型,在该家族中,与其他DC和HHS病例相关的基因已被排除,并且端粒酶表达和活性似乎正常。患者血液白细胞中的端粒严重缩短,但原代成纤维细胞中的端粒长度正常。然而,这些成纤维细胞中相当一部分端粒激活了DDR,这表明它们处于解帽状态。此外,患者血细胞和成纤维细胞中的端粒3'端悬突减少,这与两种细胞类型共有的端粒结构缺陷一致。

结论/意义:总之,这些结果表明这些患者的主要缺陷在于端粒结构,而非长度。我们推测这种缺陷阻碍了端粒酶接近端粒,从而导致依赖端粒酶补充端粒的血细胞中端粒加速缩短。此外,它还激活DDR并损害细胞增殖,即使在端粒长度正常的细胞如成纤维细胞中也是如此。这项工作证明了一条与端粒长度无关的途径,该途径导致了端粒功能障碍疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7603/2680952/21731b4e7fa2/pone.0005666.g001.jpg

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验