Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation.
Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation.
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DOI：
10.1038/s41467-022-35222-4
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发表时间：
2023-01-06
影响因子：
16.6
通讯作者：
Di Ruscio, Annalisa
中科院分区：
文献类型：
--
作者：
Esposito, Carla L.;Autiero, Ida;Sandomenico, Annamaria;Li, H.;Bassal, Mahmoud A.;Ibba, Maria L.;Wang, Dongfang;Rinaldi, Lucrezia;Ummarino, Simone;Gaggi, Giulia;Borchiellini, Marta;Swiderski, Piotr;Ruvo, Menotti;Catuogno, Silvia;Ebralidze, Alexander K.;Kortylewski, Marcin;de Franciscis, Vittorio;Di Ruscio, Annalisa
DNA甲基化是调节基因表达的基本表观遗传修饰。DNA甲基化异常是癌细胞中最常见的分子损伤。然而，医疗干预仅限于使用具有显著副作用和毒性的广泛作用的小分子脱甲基药物。为了允许靶向DNA去甲基化，我们整合了两种基于核酸的方法：DNMT 1相互作用RNA（DiR）和RNA适体策略。通过将RNA抑制DNMT 1的固有能力与适体平台相结合，我们产生了一流的DNMT 1靶向方法- aptaDiR。RNA-DNMT 1复合物的分子建模与生物化学和细胞测定相结合，使aptaDiR的鉴定和表征成为可能。这种RNA生物药物能够阻断DNA甲基化，损害癌细胞活力并抑制体内肿瘤生长。总的来说，我们提出了一种创新的基于RNA的方法来调节癌症或异常DNA甲基化疾病中的DNMT 1活性，并提出了第一种替代策略来克服目前批准的非特异性低甲基化方案的局限性，这将大大改善对DNA甲基化的临床干预。在这里，作者生成了一个基于RNA的平台来中和主要的表观遗传参与者DNMT 1。使用这种靶向方法，可以纠正癌症中的异常DNA甲基化。
DNA methylation is a fundamental epigenetic modification regulating gene expression. Aberrant DNA methylation is the most common molecular lesion in cancer cells. However, medical intervention has been limited to the use of broadly acting, small molecule-based demethylating drugs with significant side-effects and toxicities. To allow for targeted DNA demethylation, we integrated two nucleic acid-based approaches: DNMT1 interacting RNA (DiR) and RNA aptamer strategy. By combining the RNA inherent capabilities of inhibiting DNMT1 with an aptamer platform, we generated a first-in-class DNMT1-targeted approach – aptaDiR. Molecular modelling of RNA-DNMT1 complexes coupled with biochemical and cellular assays enabled the identification and characterization of aptaDiR. This RNA bio-drug is able to block DNA methylation, impair cancer cell viability and inhibit tumour growth in vivo. Collectively, we present an innovative RNA-based approach to modulate DNMT1 activity in cancer or diseases characterized by aberrant DNA methylation and suggest the first alternative strategy to overcome the limitations of currently approved non-specific hypomethylating protocols, which will greatly improve clinical intervention on DNA methylation. Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
2.9
作者：
Abdiche, Yasmina;Malashock, Dan;Pons, Jaurne
通讯作者：
Pons, Jaurne
DOI：
10.1007/978-1-4939-3197-2_3
发表时间：
2016-01-01
期刊：
NUCLEIC ACID APTAMERS
影响因子：
--
作者：
Catuogno, Silvia;Esposito, Carla Lucia;de Franciscis, Vittorio
通讯作者：
de Franciscis, Vittorio