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首页> 外文期刊>Journal of Molecular Biology >A Mechanistic Framework for Co-transcriptional Folding of the HDV Genomic Ribozyme in the Presence of Downstream Sequence.
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A Mechanistic Framework for Co-transcriptional Folding of the HDV Genomic Ribozyme in the Presence of Downstream Sequence.

机译：在下游序列的存在下，HDV基因组核酶的共转录折叠的机械框架。

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摘要

Hepatitis delta virus (HDV) is a circular pathogenic RNA that uses self-cleavage by closely related 84nt genomic and antigenomic ribozymes to facilitate the replication of its genome. Downstream of each ribozyme is a stretch of nucleotides termed the attenuator that functions to base-pair with and unfold the ribozyme into a rod-like fold. The competing rates of RNA synthesis, ribozyme folding and cleavage, and rod folding are therefore likely to affect the efficiency of co-transcriptional self-cleavage. In these studies, co-transcriptional folding of the genomic ribozyme was assayed in vitro by monitoring co-transcriptional self-cleavage of transcripts having variable lengths of sequence downstream of the ribozyme. Co-transcriptional cleavage data were simulated successfully only with kinetic models in which cleavage-inactive channels were populated during transcription. Partitioning to and escape from these channels was influenced, in part, by whether the available attenuator sequence could form structures with the ribozyme, and by the stability of such structures. Surprisingly, only 23nt of attenuator were needed for strong inactivation of cleavage. Self-cleavage of certain 3'-virus-containing sequences could be restored, partially, by renaturation; however, self-cleavage of transcripts with a full-length attenuator could not be restored efficiently by renaturation in vitro. This suggests that in the presence of the attenuator, the cleavage-active ribozyme fold is not the thermodynamically most stable species. In accordance with this model, the efficiency of self-cleavage of the ribozyme followed by a full-length attenuator was increased by decreasing the rate of transcription. These results suggest that, in the absence of additional factors, efficient co-transcriptional cleavage of the full-length genomic HDV RNA may require cleavage to occur prior to synthesis of the attenuator.
机译：三角洲肝炎病毒（HDV）是一种环状致病性RNA，利用紧密相关的84nt基因组和反基因组核酶进行自我切割，以促进其基因组的复制。每个核酶的下游是被称为衰减子的一段核苷酸，其功能是与核酶碱基配对并将其展开为杆状折叠。因此，RNA合成，核酶折叠和切割以及杆折叠的竞争速率可能会影响共转录自我切割的效率。在这些研究中，通过监测核酶下游序列长度可变的转录本的共转录​​自切割，在体外测定了基因组核酶的共转录折叠。仅使用动力学模型成功地模拟了共转录切割数据，在该动力学模型中，转录过程中存在切割非活性通道。这些通道的分配和逃逸在一定程度上受到可用衰减序列是否可以与核酶形成结构以及这种结构的稳定性的影响。出乎意料的是，仅需要23nt的衰减器即可使切割强烈失活。某些含有3'-病毒的序列的自我切割可通过复性而部分恢复。但是，用全长衰减器对转录本进行的自我切割不能通过体外复性有效地恢复。这表明在存在衰减器的情况下，具有裂解活性的核酶折叠不是热力学上最稳定的物种。根据该模型，通过降低转录速率，可以增加核酶的自我切割效率，继之以全长的衰减子。这些结果表明，在没有其他因素的情况下，全长基因组HDV RNA的有效共转录切割可能需要在合成减毒剂之前进行切割。

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