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首页> 外文期刊>Biochemistry >Single-Molecule Analysis of the Human Telomerase RNA3 Effect of Dyskeratosis Congenita Mutations
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Single-Molecule Analysis of the Human Telomerase RNA3 Effect of Dyskeratosis Congenita Mutations

机译：人端粒酶先天性突变的端粒酶RNA3效应的单分子分析

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ABSTRACT: It has been proposed that human telomerase RNA (hTR) interacts with dyskerin, prior tonassembly of the telomerase holoenzyme. The direct interaction of dyskerin and hTR has not beenndemonstrated and is an experimentally challenging research problem because of difficulties in expressingnand purifying dyskerin in quantities that are useful for biophysical analysis. By orthogonally labeling dyskerinnand hTR, we have been able to employ single-molecule two-color coincidence detection (TCCD) to observendirectly the formation of a dyskerin 3nhTR complex. By systematic deletion of hTR subdomains, we havengained insights into theRNAsites required for interaction with dyskerin.We then investigatedmutated formsnof hTR and dyskerin that are associated with dyskeratosis congenita (DC), on the basis of clinical geneticsnstudies, for their effects on the dyskerin 3nhTR interaction. Dyskerin mutations associated with X-linked DCnresulted in significant impairment of the dyskerin 3nhTR interaction, whereas mutations in hTR associatednwith autosomal dominant (AD) DC did not affect the interaction. We propose that disruption of thendyskerin 3nhTR interaction may contribute to X-linked DC.
机译：摘要：有人提出，端粒酶全酶的先组装是人端粒酶RNA（hTR）与dyskerin相互作用。 dyskerin与hTR的直接相互作用尚未得到证实，并且由于难以表达和纯化可用于生物物理分析的量的dyskerin困难，因此是一个具有实验挑战性的研究问题。通过正交标记dyskerinn和hTR，我们已经能够使用单分子双色重合检测（TCCD）来直接观察dyskerin 3nhTR复合物的形成。通过系统性地删除hTR亚结构域，我们深入了解了与dyskerin相互作用所需的RNA位点，然后在临床遗传学的基础上，研究了与先天性角化不全（DC）相关的hTR和dyskerin突变形式对它们对dyskerin 3nhTR相互作用的影响。 。与X连锁DCn相关的dyskerin突变导致dyskerin 3nhTR相互作用的显着受损，而与常染色体显性（AD）DC相关的hTR突变则不影响相互作用。我们建议，那么dydyskerin 3nhTR相互作用的破坏可能有助于X链接的DC。

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  • 来源
    《Biochemistry》 |2009年第46期|p.10858-10865|共8页
  • 作者

    Beth Ashbridge Angel Orte Justin A. Yeoman Michael Kirwan Tom Vulliamy Inderjeet Dokal David Klenerman* r and Shankar Balasubramanian;

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    ‡University Chemical Laboratories, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.,§School of ClinicalMedicine, University of Cambridge, Cambridge CB2 0SP, U.K., and ) Centre for Paediatrics, Institute of Cell andMolecular Science,Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London E1 2AT, U.K.^These authors contributed equally to this work.@Present address: Department of Physical Chemistry,Faculty of Pharmacy, CampusCartuja, Granada 18071, Spain.#Present address:National Centre for BiologicalSciences, Tata Institute of Fundamental Research, UAS GKVK, Bellary Road, Bangalore 560 065, India.rJoint senior authorship.;

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