DNA序列特异性聚酰胺可减轻与弗里德赖希共济失调中长GAA.TTC重复序列相关的转录抑制。
DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA.TTC repeats in Friedreich's ataxia.
作者信息
Burnett Ryan, Melander Christian, Puckett James W, Son Leslie S, Wells Robert D, Dervan Peter B, Gottesfeld Joel M
机构信息
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
出版信息
Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11497-502. doi: 10.1073/pnas.0604939103. Epub 2006 Jul 20.
Abstract
The DNA abnormality found in 98% of Friedreich's ataxia (FRDA) patients is the unstable hyperexpansion of a GAA.TTC triplet repeat in the first intron of the frataxin gene. Expanded GAA.TTC repeats result in decreased transcription and reduced levels of frataxin protein in affected individuals. Beta-alanine-linked pyrrole-imidazole polyamides bind GAA.TTC tracts with high affinity and disrupt the intramolecular DNA.DNA-associated region of the sticky-DNA conformation formed by long GAA.TTC repeats. Fluorescent polyamide-Bodipy conjugates localize in the nucleus of a lymphoid cell line derived from a FRDA patient. The synthetic ligands increase transcription of the frataxin gene in cell culture, resulting in increased levels of frataxin protein. DNA microarray analyses indicate that a limited number of genes are significantly affected in FRDA cells. Polyamides may increase transcription by altering the DNA conformation of genes harboring long GAA.TTC repeats or by chromatin opening.
摘要
在98%的弗里德赖希共济失调（FRDA）患者中发现的DNA异常是，在铁调素基因的第一个内含子中，GAA.TTC三联体重复序列出现不稳定的过度扩增。GAA.TTC重复序列的扩增导致受影响个体中转录减少和铁调素蛋白水平降低。β-丙氨酸连接的吡咯-咪唑聚酰胺以高亲和力结合GAA.TTC片段，并破坏由长GAA.TTC重复序列形成的粘性DNA构象的分子内DNA.DNA相关区域。荧光聚酰胺-硼二吡咯共轭物定位于源自FRDA患者的淋巴细胞系的细胞核中。合成配体在细胞培养中增加铁调素基因的转录，导致铁调素蛋白水平升高。DNA微阵列分析表明，FRDA细胞中有数量有限但显著受影响的基因。聚酰胺可能通过改变含有长GAA.TTC重复序列的基因的DNA构象或通过染色质开放来增加转录。
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