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利用与疾病相关的亚基变体研究人类端粒酶全酶的组装、活性和连续性。

Investigation of human telomerase holoenzyme assembly, activity, and processivity using disease-linked subunit variants.

机构信息

Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3200, USA.

出版信息

J Biol Chem. 2010 Feb 12;285(7):4375-86. doi: 10.1074/jbc.M109.088575. Epub 2009 Dec 17.

Abstract

After the initial discovery of human telomerase deficiency in the X-linked form of the bone marrow failure syndrome dyskeratosis congenita, mutations in genes encoding telomerase subunits have been identified in patients with a wide spectrum of disorders. Structure/function studies of disease-linked variants of human telomerase RNA (hTR) or telomerase reverse transcriptase (TERT) have exploited in vitro reconstitution of the enzyme catalytic core and/or a PCR-amplified activity assay readout that would not reflect alterations of cellular RNP assembly efficiency, telomeric primer recognition, and/or repeat addition processivity. Here we used telomerase reconstitution in vivo and direct telomeric-repeat primer extension activity assays to compare the ribonucleoprotein (RNP) assembly and activity properties of disease-linked subunit variants in holoenzyme context. Analysis of a large panel of hTR variants revealed numerous biochemical mechanisms for telomerase loss of function, including reduced association of hTR with TERT, reduced RNP catalytic activity, or loss in fidelity of telomeric repeat synthesis. An absolute correlation exists between hTR loss of function and hematopoietic deficiency, but there is no readily apparent telomerase deficiency imposed by an hTR variant linked to pulmonary fibrosis. Some disease-linked TERT variants have altered properties of holoenzyme assembly or repeat addition processivity, but other TERT variants linked to either pulmonary fibrosis or hematopoietic deficiency retained normal hTR interaction and RNP catalytic activity. Combined with additional hTR structure/function studies, our results establish a new resolution of insight into hTR structural requirements for hTR-TERT interaction and for the catalytic cycle of human telomerase holoenzyme.

摘要

在骨髓衰竭综合征先天性角化不良的 X 连锁形式中最初发现人类端粒酶缺乏后,已经在具有广泛疾病谱的患者中鉴定出编码端粒酶亚基的基因突变。疾病相关的人类端粒酶 RNA (hTR) 或端粒酶逆转录酶 (TERT) 变体的结构/功能研究利用体外酶催化核心的重建和/或 PCR 扩增的活性测定,该测定不会反映细胞 RNP 组装效率、端粒引物识别和/或重复添加过程性的改变。在这里,我们使用体内端粒酶重建和直接端粒重复引物延伸活性测定来比较全酶背景下疾病相关亚基变体的核糖核蛋白 (RNP) 组装和活性特性。对大量 hTR 变体的分析揭示了端粒酶功能丧失的许多生化机制,包括 hTR 与 TERT 的结合减少、RNP 催化活性降低或端粒重复合成保真度丧失。hTR 功能丧失与造血缺陷之间存在绝对相关性,但与肺纤维化相关的 hTR 变体没有明显的端粒酶缺乏。一些与疾病相关的 TERT 变体具有改变的全酶组装或重复添加过程性的特性,但与肺纤维化或造血缺陷相关的其他 TERT 变体保留了正常的 hTR 相互作用和 RNP 催化活性。结合其他 hTR 结构/功能研究,我们的结果为 hTR 结构要求建立了新的分辨率,以了解 hTR-TERT 相互作用和人类端粒酶全酶的催化循环。

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