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锁核酸(LNA)修饰对10-23脱氧核酶活性的影响。

Influence of LNA modifications on the activity of the 10-23 DNAzyme.

作者信息

Muñoz-González Marcelo, Aguilar Rodrigo, Moreno Adrian A, Cepeda-Plaza Marjorie

机构信息

Chemical Sciences Department, Universidad Andres Bello Santiago Chile.

Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello Chile.

出版信息

RSC Adv. 2025 Apr 23;15(17):13031-13040. doi: 10.1039/d5ra00161g. eCollection 2025 Apr 22.

Abstract

The 10-23 DNAzyme is a catalytic DNA molecule that efficiently cleaves RNA in the presence of divalent cations such as Mg or Ca. Following their discovery, the 10-23 DNAzymes demonstrated numerous advantages that quickly led them to be considered powerful molecular tools for the development of gene-silencing tools. In this study, we evaluate the efficiency of the 10-23 DNAzyme and an LNA-modified analog in cleaving human MALAT1, an RNA overexpressed in cancer cells. First, we perform assays using a 20 nt RNA fragment from the MALAT1 sequence, with 2 mM and 10 mM Mg and Ca as cofactors, to evaluate how LNA modifications influence catalytic activity. We found that the activity is increased in the LNA-modified DNAzyme compared to the unmodified version with both cofactors, in a concentration-dependent manner. Finally, the RNA-cleaving activity of the LNA-modified, catalytically active 10-23 DNAzyme was tested in MCF7 human breast cancer cells. We found that the DNAzyme persists for up to 72 h in cells and effectively silences MALAT1 RNA in a concentration-dependent manner as early as 12 h post-transfection.

摘要

10-23脱氧核酶是一种催化性DNA分子,在诸如镁或钙等二价阳离子存在的情况下能有效切割RNA。自被发现以来,10-23脱氧核酶展现出众多优势,这使其很快被视为用于开发基因沉默工具的强大分子工具。在本研究中,我们评估了10-23脱氧核酶和一种锁核酸(LNA)修饰的类似物切割人MALAT1(一种在癌细胞中过表达的RNA)的效率。首先,我们使用来自MALAT1序列的一个20个核苷酸的RNA片段进行实验,以2 mM和10 mM的镁和钙作为辅因子,来评估LNA修饰如何影响催化活性。我们发现,与未修饰的版本相比,在两种辅因子存在的情况下,LNA修饰的脱氧核酶的活性均以浓度依赖的方式增加。最后,在MCF7人乳腺癌细胞中测试了LNA修饰的、具有催化活性的10-23脱氧核酶的RNA切割活性。我们发现,脱氧核酶在细胞中可持续存在长达72小时,并早在转染后12小时就以浓度依赖的方式有效沉默MALAT1 RNA。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bea/12016023/09902f9845f6/d5ra00161g-f1.jpg

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