Vázquez-Ortiz Guelaguetza, Piña-Sánchez Patricia, Salcedo Mauricio
Laboratorio de Oncología Genómica, Unidad de Investigación Médica en Enfermedades Oncológicas. Hospital de Oncología, Centro Médico Nacional Siglo XXI-IMSS.
Rev Invest Clin. 2006 Jul-Aug;58(4):335-49.
Double-stranded RNA (dsRNA) induces a sequence-specific silencing in eukaryotic cells. This silencing process beggins when long dsRNA is cleaved to 21 to 26 long small RNA by means of the RNAse III-type enzyme Dicer. These small dsRNA are included into silencing effector complexes, that are targeted to complementary sequences. Small RNA dependent gene silencing can be achieved by distinct mechanisms based depending mainly on the nature of target sequences and on the proteins present in the effector complex. The route of interference RNA (RNAi) begins when Dicer yields small interference RNA (siRNA) that bind to complementary mRNA for its degradation, forming the RISC complex. siRNA are naturally formed from transposons and dsRNA viruses during its replication, as well as from other bidirectional transcribed repetitive sequences. Some of the enzymes thar are part of the RNAi machinery, including Dicer, are encoded by multigene families in many species, that also play a role in other mechanisms of RND-dependent gene silencing. MicroRNA's (miRNA) are other small RNA's that can induce gene silencing at the mRNA level. These are formed in a general manner when Dicer process hairpin structures resulting from the transcription of non-coding sequences from plant and animal genomes. miRNA's are integrated into a RISC-like complex, after which, depending on their degree of complementarity with target mRNA, can either repress translation or induce mRNA degradation. miRNA-dependent silencing is essential for the development of multicellular organisms. Artificial RNAi induction by means of siRNA or miRNA is being used as a tool to inactivate gene expression in culture cells and in living organisms. This review focuses on the progress in the understanding of the mechanisms involved in gene regulation by RNA in animals and details some current efforts to apply theses phenomena as a tool in research and in the therapeutic of human diseases.
双链RNA(dsRNA)可在真核细胞中诱导序列特异性沉默。当长双链RNA被RNA酶III型酶Dicer切割成21至26个核苷酸长的小RNA时,这个沉默过程就开始了。这些小双链RNA被纳入沉默效应复合物中,该复合物靶向互补序列。小RNA依赖性基因沉默可通过不同机制实现,主要取决于靶序列的性质和效应复合物中存在的蛋白质。干扰RNA(RNAi)途径始于Dicer产生小干扰RNA(siRNA),siRNA与互补的mRNA结合以进行降解,形成RNA诱导沉默复合体(RISC)。siRNA在转座子和dsRNA病毒复制过程中自然形成,也来自其他双向转录的重复序列。RNAi机制中的一些酶,包括Dicer,在许多物种中由多基因家族编码,它们在其他RNA依赖性基因沉默机制中也发挥作用。微小RNA(miRNA)是其他可在mRNA水平诱导基因沉默的小RNA。当Dicer加工由植物和动物基因组中非编码序列转录产生的发夹结构时,它们以一般方式形成。miRNA被整合到类似RISC的复合物中,之后,根据它们与靶mRNA的互补程度,可抑制翻译或诱导mRNA降解。miRNA依赖性沉默对于多细胞生物体的发育至关重要。通过siRNA或miRNA进行人工RNAi诱导正被用作一种工具,用于使培养细胞和活生物体中的基因表达失活。本综述重点关注动物中RNA参与基因调控机制的理解进展,并详细介绍了目前将这些现象应用于研究和人类疾病治疗的一些努力。