Identification of the toxic 6mer seed consensus for human cancer cells.
Identification of the toxic 6mer seed consensus for human cancer cells.
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DOI：
10.1038/s41598-022-09051-w
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发表时间：
2022-03-24
影响因子：
4.6
通讯作者：
Peter ME
中科院分区：
文献类型：
--
作者：
Patel M;Bartom ET;Paudel B;Kocherginsky M;O'Shea KL;Murmann AE;Peter ME
6 mer种子毒性是一种新的细胞死亡机制，通过触发生存基因消除诱导的死亡（DISE）来杀死癌细胞。它基于在其引导链的位置2-7中具有特定的富含G的核苷酸组成的si-或shRNA。在两个人和两个小鼠细胞系上的4096个6聚体种子的阵列筛选鉴定出富含G的6聚体为毒性最大的种子。我们现在已经测试了另外两种细胞系，一种人和一种小鼠，确定GGGGGC共识是人类癌细胞毒性最大的平均6聚体种子，而对小鼠癌细胞的毒性略低。RNA Seq和生物信息学分析表明，含有GGGGGC种子（siGGGGGC）的siRNA通过靶向主要位于一组对细胞存活至关重要的基因的3′ UTR中的GCCCCC种子匹配对癌细胞具有毒性。我们已经鉴定了该种子靶向的几个基因，并证明了GCCCCC种子匹配的直接和特异性靶向，其在这些3′ UTR中的GCCCCC种子匹配突变后减弱。我们的数据显示siGGGGGC通过其miRNA样活性杀死癌细胞，并指出含有这种种子的人工miRNA、si-或shRNA作为潜在的新癌症治疗剂。
6mer seed toxicity is a novel cell death mechanism that kills cancer cells by triggering death induced by survival gene elimination (DISE). It is based on si- or shRNAs with a specific G-rich nucleotide composition in position 2–7 of their guide strand. An arrayed screen of 4096 6mer seeds on two human and two mouse cell lines identified G-rich 6mers as the most toxic seeds. We have now tested two additional cell lines, one human and one mouse, identifying the GGGGGC consensus as the most toxic average 6mer seed for human cancer cells while slightly less significant for mouse cancer cells. RNA Seq and bioinformatics analyses suggested that an siRNA containing the GGGGGC seed (siGGGGGC) is toxic to cancer cells by targeting GCCCCC seed matches located predominantly in the 3′ UTR of a set of genes critical for cell survival. We have identified several genes targeted by this seed and demonstrate direct and specific targeting of GCCCCC seed matches, which is attenuated upon mutation of the GCCCCC seed matches in these 3′ UTRs. Our data show that siGGGGGC kills cancer cells through its miRNA-like activity and points at artificial miRNAs, si- or shRNAs containing this seed as a potential new cancer therapeutics.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
11.2
作者：
Patel M;Wang Y;Bartom ET;Dhir R;Nephew KP;Matei D;Murmann AE;Lengyel E;Peter ME
通讯作者：
Peter ME
影响因子：
64.5
作者：
Stark, A;Brennecke, J;Cohen, SM
通讯作者：
Cohen, SM
影响因子：
64.5
作者：
Lewis, BP;Shih, IH;Burge, CB
通讯作者：
Burge, CB
影响因子：
4.7
作者：
Chan, John K.;Blansit, Kevin;Bourguignon, Lilly Y. W.
通讯作者：
Bourguignon, Lilly Y. W.