亚精胺抑制核糖体DNA转录

Spermidine inhibits rDNA transcription

核糖体是细胞内合成蛋白的唯一细胞器,主要由核糖体RNA(ribosomal RNA,rRNA)和核糖体蛋白组装形成.rDNA转录生成rRNA在细胞内的核仁处完成,是核糖体生物发生的重要限速步骤之一.在正常细胞内,核糖体DNA(ribosomal DNA,rDNA)的转录活性受到营养状态的严密调控.而在癌细胞内,癌基因的激活、抑癌基因的失活和生长相关信号通路的失调等多种不同的机制均可导致rDNA的转录绕过营养状态的控制.癌细胞内异常激活的rDNA转录是癌细胞快速生长、增殖的必要前提,也是癌细胞的共有特征之一.抑制癌细胞内异常激活的r DNA转录有望开发出新的抗癌药物.我们既往的研究揭示,肿瘤蛋白p53诱导核蛋白2(tumor protein p53 inducible nuclear protein 2,TP53INP2)的核仁定位是其促进rDNA转录的重要前提,可用来指示细胞内的rDNA转录活性.本研究发现,天然活性成分亚精胺可抑制TP53INP2的核仁定位,并显著降低细胞的rDNA转录活性.机制研究表明,亚精胺可抑制蛋白激酶雷帕霉素靶蛋白复合物1(mechanistic target of rapamycin complex 1,mTORC1)的必需亚基Raptor的乙酰化并降低细胞内m TORC1的活性,进而抑制r DNA的转录.功能研究揭示,亚精胺可显著抑制蛋白的合成和细胞的增殖.本研究提示,抑制细胞内的r DNA转录活性可能是亚精胺发挥抗癌作用的重要机制之一.

Ribosome,composed of ribosomal RNAs(rRNAs)and ribosomal proteins,is the only organelle in the cell for protein synthesis.As the structural molecules,rRNAs transcribed from ribosomal DNA(rDNA)make up over half of the mass of the ribosome.There are millions of ribosomes in every single mammalian cell.To meet the huge demand for the production of rRNAs,the genes of rDNA in the genome are highly repetitive and contain hundreds to thousands of copies.The production of rRNAs is a multi-stage process,including synthesis,processing and modifications,among which rDNA transcription at the nucleolus is one of the key rate-limiting steps.In normal cells,rDNA transcription is tightly controlled by nutrient-sensing pathways,such as mechanistic target of rapamycin complex 1(mTORC1)and AMP-activated protein kinase(AMPK),linking rDNA transcription activity to nutrient availability.By contrast,in cancer cells,various mechanisms,such as activation of oncogenes,inactivation of tumor suppressors,and dysregulation of nutrient-sensing pathways,help cancer cells bypass the restriction of nutrients and result in the hyperactivation of rDNA transcription.Importantly,the hyperactivation of rDNA transcription is required for cancer cells to support their sustainable upregulated growth and proliferation.Intervention of the hyperactivation of rDNA transcription in cancer cells has emerged as a promising strategy for anticancer therapy.Previously,we reported that tumor protein p53 inducible nuclear protein 2(TP53INP2)at the nucleolus promotes rDNA transcription by driving the assembly of the RNA polymerase I preinitiation complex at the rDNA promoter region.Interestingly,nucleolar localization is required for TP53INP2 to stimulate rDNA transcription,suggesting that the nucleolar localization of TP53INP2 can be used as an indicator of rDNA transcription activity in the cell.In this study,we showed that treatment of the cells with spermidine,a naturally occurring polyamine,can markedly eliminate the nucleolar localization of TP53INP2.Consistent with this observation,we found that spermidine treatment suppresses cellular rDNA transcription and leads to a significant reduction of the precursor rRNA transcript 47S rRNA.Mechanistically,spermidine inhibits the activity of cellular mTORC1,the master upstream activator of rDNA transcription,through a mechanism that is partially dependent on the decrease of the acetylation of regulatory-associated protein of mTOR(Raptor),the necessary subunit of mTORC1.Functionally,spermidine suppresses protein synthesis and cell proliferation.Taken together,our findings identify spermidine as a novel inhibitor of rDNA transcription and suggest that the inhibition of rDNA transcription may be an important mechanism by which spermidine exerts its anticancer effect.Of note,spermidine has been reported to activate AMPK to inhibit mTORC1.There seem to be several different mechanisms utilized by spermidine to regulate mTORC1 activity.It is noteworthy that spermidine supplementation has been demonstrated to modulate aging,extend lifespan,and ameliorate aging-related diseases in various animal models,including worms,flies,and mice.It would be interesting to investigate whether the inhibition of rDNA transcription is one of the mechanisms through which spermidine exerts its anti-aging effect.