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A dual-activity topoisomerase complex regulates mRNA translation and turnover
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2022-06-24 , DOI: 10.1093/nar/gkac538
Shuaikun Su 1 , Yutong Xue 1 , Alexei Sharov 1 , Yongqing Zhang 1 , Seung Kyu Lee 1 , Jennifer L Martindale 1 , Wen Li 2 , Wai Lim Ku 3 , Keji Zhao 3 , Supriyo De 1 , Weiping Shen 1 , Payel Sen 1 , Myriam Gorospe 1 , Dongyi Xu 2 , Weidong Wang 1
Affiliation  

Topoisomerase 3β (TOP3B) and TDRD3 form a dual-activity topoisomerase complex that interacts with FMRP and can change the topology of both DNA and RNA. Here, we investigated the post-transcriptional influence of TOP3B and associated proteins on mRNA translation and turnover. First, we discovered that in human HCT116 colon cancer cells, knock-out (KO) of TOP3B had similar effects on mRNA turnover and translation as did TDRD3-KO, while FMRP-KO resulted in rather distinct effects, indicating that TOP3B had stronger coordination with TDRD3 than FMRP in mRNA regulation. Second, we identified TOP3B-bound mRNAs in HCT116 cells; we found that while TOP3B did not directly influence the stability or translation of most TOP3B target mRNAs, it stabilized a subset of target mRNAs but had a more complex effect on translation–enhancing for some mRNAs whereas reducing for others. Interestingly, a point mutation that specifically disrupted TOP3B catalytic activity only partially recapitulated the effects of TOP3B-KO on mRNA stability and translation, suggesting that the impact of TOP3B on target mRNAs is partly linked to its ability to change topology of mRNAs. Collectively, our data suggest that TOP3B–TDRD3 can regulate mRNA translation and turnover by mechanisms that are dependent and independent of topoisomerase activity.

中文翻译:

双活性拓扑异构酶复合物调节 mRNA 翻译和转换

拓扑异构酶 3β (TOP3B) 和 TDRD3 形成一种双活性拓扑异构酶复合物,它与 FMRP 相互作用,可以改变 DNA 和 RNA 的拓扑结构。在这里,我们研究了 TOP3B 和相关蛋白对 mRNA 翻译和转换的转录后影响。首先,我们发现在人类 HCT116 结肠癌细胞中,TOP3B 的敲除 (KO) 对 mRNA 转换和翻译的影响与 TDRD3-KO 相似,而 FMRP-KO 产生的影响相当明显,表明 TOP3B 具有更强的协调性与 TDRD3 相比,FMRP 在 mRNA 调节中的作用。其次,我们在 HCT116 细胞中鉴定了 TOP3B 结合的 mRNA;我们发现虽然 TOP3B 不直接影响大多数 TOP3B 目标 mRNA 的稳定性或翻译,它稳定了目标 mRNA 的一个子集,但对翻译有更复杂的影响——增强某些 mRNA 而减少其他 mRNA。有趣的是,特异性破坏 TOP3B 催化活性的点突变仅部分概括了 TOP3B-KO 对 mRNA 稳定性和翻译的影响,表明 TOP3B 对靶 mRNA 的影响部分与其改变 mRNA 拓扑结构的能力有关。总的来说,我们的数据表明 TOP3B–TDRD3 可以通过依赖和独立于拓扑异构酶活性的机制调节 mRNA 翻译和转换。表明 TOP3B 对目标 mRNA 的影响部分与其改变 mRNA 拓扑结构的能力有关。总的来说,我们的数据表明 TOP3B–TDRD3 可以通过依赖和独立于拓扑异构酶活性的机制调节 mRNA 翻译和转换。表明 TOP3B 对目标 mRNA 的影响部分与其改变 mRNA 拓扑结构的能力有关。总的来说,我们的数据表明 TOP3B–TDRD3 可以通过依赖和独立于拓扑异构酶活性的机制调节 mRNA 翻译和转换。
更新日期:2022-06-24
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