Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3.
Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3.
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通过靶向 RNA 聚合酶 I 和 Rrn3 之间界面的小分子肽选择性抑制 rDNA 转录。
DOI：
10.1158/1541-7786.mcr-14-0229
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Rothblum,LawrenceI
中科院分区：
文献类型：
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作者：
Rothblum,Katrina;Hu,Qiyue;Penrod,Yvonne;Rothblum,LawrenceI
聚合酶I相关因子Rrn3和RNA聚合酶I的43-kDa亚基之间的接口是必不可少的招聘Pol I的preinitiation复合物上的rDNA promoter.In silicoanalysis确定了一个进化保守的22个氨基酸的rpa43内的肽，这是必要的和足够的介导rpa43和Rrn3之间的相互作用。该肽在体外抑制rDNA的转录，而对照肽没有。为了确定肽在培养细胞中的作用，将肽偶联到HIV TAT肽以促进转导到细胞中。野生型肽，而不是对照肽，抑制Pol I转录和细胞分裂。此外，该肽诱导细胞死亡，与"核仁应激"导致肿瘤细胞死亡的其他观察结果一致。22聚体是rDNA转录的小分子抑制剂，其对Rrn3和rpa43之间的相互作用具有特异性，因此它代表了干扰细胞生长的原始方式。© 2014 AACR.
The interface between the polymerase I–associated factor Rrn3 and the 43-kDa subunit of RNA polymerase I is essential to the recruitment of Pol I to the preinitiation complex on the rDNA promoter.In silicoanalysis identified an evolutionarily conserved 22 amino acid peptide within rpa43 that is both necessary and sufficient to mediate the interaction between rpa43 and Rrn3. This peptide inhibited rDNA transcriptionin vitro, while a control peptide did not. To determine the effect of the peptide in cultured cells, the peptide was coupled to the HIV TAT peptide to facilitate transduction into cells. The wild-type peptide, but not control peptides, inhibited Pol I transcription and cell division. In addition, the peptide induced cell death, consistent with other observations that “nucleolar stress” results in the death of tumor cells. The 22mer is a small-molecule inhibitor of rDNA transcription that is specific for the interaction between Rrn3 and rpa43, as such it represents an original way to interfere with cell growth.Implications:These results demonstrate a potentially novel pharmaceutical target for the therapeutic treatment of cancer cells.Mol Cancer Res; 12(11); 1586–96. ©2014 AACR.