更新于：2024-05-01

DDX21

DExD-box helicase 21

更新于：2024-05-01

基本信息

别名

DDX21、DEAD box protein 21、DExD-box helicase 21

+ [7]

简介

RNA helicase that acts as a sensor of the transcriptional status of both RNA polymerase (Pol) I and II: promotes ribosomal RNA (rRNA) processing and transcription from polymerase II (Pol II) (PubMed:25470060, PubMed:28790157). Binds various RNAs, such as rRNAs, snoRNAs, 7SK and, at lower extent, mRNAs (PubMed:25470060). In the nucleolus, localizes to rDNA locus, where it directly binds rRNAs and snoRNAs, and promotes rRNA transcription, processing and modification. Required for rRNA 2'-O-methylation, possibly by promoting the recruitment of late-acting snoRNAs SNORD56 and SNORD58 with pre-ribosomal complexes (PubMed:25470060, PubMed:25477391). In the nucleoplasm, binds 7SK RNA and is recruited to the promoters of Pol II-transcribed genes: acts by facilitating the release of P-TEFb from inhibitory 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes (PubMed:25470060). Functions as cofactor for JUN-activated transcription: required for phosphorylation of JUN at 'Ser-77' (PubMed:11823437, PubMed:25260534). Can unwind double-stranded RNA (helicase) and can fold or introduce a secondary structure to a single-stranded RNA (foldase) (PubMed:9461305). Together with SIRT7, required to prevent R-loop-associated DNA damage and transcription-associated genomic instability: deacetylation by SIRT7 activates the helicase activity, thereby overcoming R-loop-mediated stalling of RNA polymerases (PubMed:28790157). Involved in rRNA processing (PubMed:14559904, PubMed:18180292). May bind to specific miRNA hairpins (PubMed:28431233). Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1 (By similarity).

关联

100 项与 DDX21 相关的临床结果

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100 项与 DDX21 相关的转化医学

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0 项与 DDX21 相关的专利（医药）

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144

项与 DDX21 相关的文献（医药）

2024-02-20·Cancer letters

Lnc-PLCB1 is stabilized by METTL14 induced m6A modification and inhibits Helicobacter pylori mediated gastric cancer by destabilizing DDX21.

Article

作者: Mingjie Chang ; Qiyu Sun ; Xixi Cui ; Yuqiong Wang ; Jiayi Liu ; Zenghui Sun ; Juchao Ren ; Yundong Sun ; Lihui Han ; Wenjuan Li

Helicobacter pylori (H. pylori) infection is considered to be an important factor in gastric cancer (GC). Long noncoding RNA (lncRNA) and m6A modification are involved in the occurrence and development of GC, but the role of lncRNA m6A modification in the development of GC mediated by H. pylori is still unclear. Here, we found that H. pylori infection downregulated the expression of lnc-PLCB1 through METTL14-mediated m6A modification and IRF2-mediated transcriptional regulation. Overexpression of lnc-PLCB1 inhibited the proliferation and migration of GC cells, while downregulation of lnc-PLCB1 promoted the proliferation and migration ability of GC cells. In addition, clinical analysis showed that lnc-PLCB1 is lower in GC tissues than in normal tissues. Further study found that lnc-PLCB1 reduced the protein stability of its binding protein DEAD-box helicase 21 (DDX21) and then downregulated the expression of CCND1 and Slug, thereby playing tumour suppressing role in the occurrence and development of GC. In conclusion, the METTL14/lnc-PLCB1/DDX21 axis plays an important role in H. pylori-mediated GC, and lnc-PLCB1 can be used as a new target for GC treatment.

2024-01-01·Frontiers in microbiology

DEAD-box RNA helicase 21 interacts with porcine circovirus type 2 Cap protein and facilitates viral replication.

Article

作者: Jianwei Zhou ; Jie Zhao ; Haoyu Sun ; Beining Dai ; Ning Zhu ; Qianhong Dai ; Yonghui Qiu ; Dedong Wang ; Yongqiu Cui ; Jinshuo Guo ; Xufei Feng ; Lei Hou ; Jue Liu

Porcine circovirus type 2 (PCV2) is the etiological agent of PCV2-associated diseases that pose a serious threat to the swine industry. PCV2 capsid (Cap) protein has been shown to interact with DEAD-box RNA helicase 21 (DDX21), an important protein that regulates RNA virus replication. However, whether the interaction between DDX21 and the PCV2 Cap regulates PCV2 replication remains unclear. Herein, by using western blotting, interaction assays, and knockdown analysis, we found that PCV2 infection induced the cytoplasmic relocation of DDX21 from the nucleolus in cultured PK-15 cells. Moreover, the nuclear localization signal (NLS) of PCV2 Cap interacted directly with DDX21. The NLS of PCV2 Cap and ⁷⁶³GSRSNRFQNK⁷⁷² residues at the C-terminal domain (CTD) of DDX21 were essential for the dual interaction. Upon shRNA-mediated DDX21 depletion in PK-15 cells, we observed impaired PCV2 replication via a lentivirus-delivered system, as evidenced by decreased levels of viral protein expression and virus production. In contrast, the replication of PCV2 increased in transiently DDX21-overexpressing cells. Our results indicate that DDX21 interacts with PCV2 Cap and plays a crucial role in virus replication. These results provide a reference for developing novel potential targets for prevention and control of PCV2 infection.

2023-12-01·Anticancer research

Disclosing Potential Therapeutic Targets Associated With Osimertinib Resistance in the Non-small Cell Lung Cancer Cell Line H1975.

Article

作者: Xuexia Tong ; Rui Zhang ; Rong Sun ; Weizhi Yang ; Jinhan Sun ; Juan Chen ; Fang Li

BACKGROUND/AIM:

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is a highly effective and valuable treatment option for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, such as T790M. However, acquired resistance ultimately limits its clinical application. In this study, we aimed to identify potential targets for overcoming osimertinib resistance.

MATERIALS AND METHODS:

The H1975/OSI cell line was induced in vitro through intermittent induction. Cell activity was measured using a cell counting kit-8 assay. Uni-omics and multi-omics analyses were conducted on the transcriptomic and proteomic (4D label-free) expression profiles, which involved differential expression analysis, GO functional annotation and KEGG pathway enrichment analysis, as well as correlation analysis of transcription factors and PPI network.

RESULTS:

H1975/OSI cells showed resistance towards osimertinib with IC50 values approximately 5.25-fold higher than H1975 cells. A total of 2519 genes were found to be differentially expressed genes (DEGs) and 1533 proteins were found to be differentially abundant proteins (DAPs). Furthermore, 147 genes that were differentially expressed at both the transcription and protein levels (TPGs) were identified as being differentially expressed in both the transcriptome and proteome. It was revealed that many pathways related to the structure and function of ribosomes, as well as metabolites, were altered. The highest connectivity genes of 147 TPGs included NOP56, DDX21, PDCD11, CCNB1, and TOP2A. The hub genes of the transcriptional regulatory network included DDX21, KPNA2, DDX5, BRCA1, LMNB1, and HIF1A.

CONCLUSION:

Collectively, our high-throughput analysis uncovered functional properties that interacted with gene signatures of H1975/OSI cells, and highlighted certain pathways and eleven hub genes that may be the potential targets for improving clinical osimertinib resistance.

项与 DDX21 相关的新闻（医药）

2024-04-06

·生物探索

Mol Cell | 中国科学院任捷/杨运桂揭示共转录m6A修饰建立机制及功能

引言N6-甲基腺苷(m6 A)是调节人类细胞多种生物过程的关键RNA修饰，但其共转录沉积和功能尚不清楚。2024年4月2日，中国科学院北京基因组研究所任捷及杨运桂共同通讯在Molecular Cell 在线发表题为“DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability”的研究论文，该研究发现了RNA解旋酶DDX21在指导新生RNA上的m6 A修饰以进行共转录调控方面具有先前未被认识到的作用。DDX21通过识别R环与METTL3相互作用，共同募集到染色质上，当新生转录物杂交到模板DNA链上时，R环可以共同转录形成。DDX21的解旋酶活性对于METTL3介导的m6 A在新生RNA上的沉积是必需的。在转录终止区，这种联系促进了XRN2介导的RNAPII转录终止。任何这些步骤的破坏，包括DDX21、METTL3或它们的酶活性的丧失，都会导致有缺陷的终止，从而诱导DNA损伤。因此，该研究认为R-loop-DDX21-METTL3连接弥补了m6 A共转录修饰、协调转录终止和基因组稳定性的缺失环节。m6 A是哺乳动物信使RNA (mRNA)中含量最多的修饰物。它是影响mRNA整个生命周期的关键表转录组调控层，包括mRNA前剪接、3’端加工、核输出、翻译、稳定和衰变。由METTL3、METTL14、WTAP、VIRMA、HAKAI、ZC3H13和RBM15组成的甲基转移酶复合物(MTC)催化。MTC与外显子连接复合物的抑制作用一起，共同塑造了m6 A的分布轮廓，其分布在基因体上，并表现出对停止密码子的特异性富集。这种模式是在共转录过程中建立的，并在稳定状态下保持不变。尽管有这些重要的功能和已确立的模式，关于MTC如何协同转录的证据仍然很少，尽管有一些迹象体外研究已经证明了DRACH的保守基序(D = a, G或U;R = A或G;H = A, C，或U)表示MTC的酶活性。然而，这个基序很难解释其分布模式，因为只有5%的基序在体内被利用，表明在新生转录本转录过程中，存在未知的分子决定因素来决定m6 A在新生转录本上的安装。此外，它在调节转录本身中的作用已经开始被揭示，共转录安装的m6 A可能具有不同的功能，这取决于它安装的位置。然而，其安装的上游决定因素和其功能的下游效应在很大程度上仍然未知。模式图（Credit: Molecular Cell）DDX21是DEAD-box亚家族的一员，是一种多任务RNA解旋酶，它利用ATP水解产生的能量来解绕结构RNA分子，从而使下游RNA加工或RNA -蛋白复合物的重塑DDX21与各种RNA底物结合，如rRNA、snoRNA、7SK和核酸结构，包括通常由新生RNA与模板DNA杂交共同转录形成的R环。DDX21参与了广泛的生物过程，包括核糖体生物发生的多个步骤，RNA聚合酶II (RNAPII)介导的转录调节，以及表皮分化的细胞葡萄糖水平感知等。这些多面功能与许多发育缺陷和疾病(包括癌症)有关，可能反映了DDX21可能存在于多种复合物中以介导相应的细胞过程。尽管越来越多的证据表明它的重要作用，但目前还不清楚这种解旋酶是否以及如何参与决定和促进m6 A的安装。在这里。该研究发现了R-loop-DDX21-METTL3-m6 A的一个以前未知的调控轴，它通过协调募集和酶活性的联系，弥补了共转录甲基化及其调控作用的缺失环节，并协调了转录活动与基因组稳定性的关系。这个分子轴为了解m6 A在共转录调控中的基础和功能提供了重要的机制见解。切割该轴的中介结构域和关键酶活性可能为调节m6 A表转录组提供重要靶点，从而促进转录终止并维持基因组稳定性。这些发现揭示了协同转录的m6 A沉积与下游调控结果之间的相互作用，并可能有助于开发创新策略来解决与m6 A代谢失调相关的疾病。原文链接https://www-cell-com.libproxy1.nus.edu.sg/molecular-cell/abstract/S1097-2765(24)00188-6责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

信使RNA临床1期

2023-03-13

·生物谷

陈玲玲研究组Nature:核仁新结构调控核糖体RNA末端加工机制取得进展

陈玲玲研究组长期致力于lncRNA代谢与功能的研究。前期研究通过non-poly(A)测序（Yang et al., Genome Biol 2011）发现一类新型lncRNA家族。中国科学院分子细胞科学卓越创新中心（生物化学与细胞生物学研究所）陈玲玲研究组在《自然》（Nature）上，在线发表了题为Nucleolar URB1 ensures 3' ETS rRNA removal to prevent exosome surveillance的研究论文。该工作利用高分辨率活细胞显微成像技术，通过筛选200个核仁候选蛋白质发现12个在纤维中心/致密纤维组分（FC/ DFC）外围富集的蛋白质，并命名该区域为致密纤维组分外侧区域（periphery of DFC,PDFC）。研究解析发现，位于PDFC的URB1（unhealthy ribosome protein 1）是一种具有非流动特征的核仁蛋白质，对维持PDFC的完整性、锚定pre-rRNA 3’端及保证其正确折叠和加工起到重要作用。该工作揭示了核仁的超微精细结构，为解析核仁的功能和结构提供了全新见解，并为探索核仁蛋白质在pre-rRNA加工中的功能协调以及对核糖体生成和胚胎发育影响提供了全新思路。陈玲玲研究组长期致力于lncRNA代谢与功能的研究。前期研究通过non-poly(A)测序（Yang et al., Genome Biol 2011）发现一类新型lncRNA家族。它们来自内含子，两端以snoRNA结尾，被命名为sno-lncRNA（Yin et al., Molecular Cell 2012）。SLERT是其中一个sno-lncRNA，完全定位在细胞核仁（Xing et al., Cell 2017）。核仁是细胞核内一个复杂且高度动态变化的无膜亚结构，是细胞核内核糖体RNA（ribosomal RNA，rRNA）的加工厂。它在调节rRNA的转录、加工以及核糖体亚基组装中具有重要作用。核仁在形态上由内而外可以分为三层结构——多个纤维中心（Fibrillar Center，FC）和致密纤维组分（Dense Fibrillar Component，DFC）形成球状结构镶嵌在颗粒区（Granular Component，GC）内。既往研究表明，SLERT直接结合核仁蛋白DDX21并调控其形成的环状结构的大小进而促进RNA聚合酶I转录（Xing et al., Cell 2017；Wu et al., Science 2021）。RNA聚合酶I转录复合物聚集在FC区域边缘对核糖体DNA（rDNA）进行转录；rRNA前体（pre-rRNA）加工蛋白质在DFC区域参与调控rRNA前体的定向转运和核仁DFC环簇状结构的组装（Yao et al., Molecular Cell 2019）。这些在FC/DFC单元产生的rRNA占细胞内总RNA的约85%，因而在FC/DFC中rRNA成熟的过程是一个受到精密调控的过程。加工修饰完成的pre-rRNA进入GC区域参与核糖体亚基的组装。核仁的重要功能毋庸置疑，但多数核仁蛋白质的精确定位及其如何参与pre-rRNA高效有序加工等基础生物学问题尚不清楚。研究利用CRISPR/Cas9技术构建了DFC/GC双色荧光蛋白质标记的参考细胞系，在此细胞系内对200个核仁候选蛋白质进行了高分辨率的活细胞成像，并筛选到140个定位在细胞核仁不同亚结构区域的蛋白质。对这140个核仁蛋白质的研究发现，12个蛋白质定位于DFC外部，形成厚度约为200 nm的球壳状新结构，被命名为PDFC。研究进一步利用光学超分辨显微成像系统性地完善了核仁的精细亚结构分析，为更好地解析核仁组织结构和工作机制奠定了重要基础。研究发现，PDFC关键蛋白质URB1具有分子量大、流动性慢的特征，对于维持PDFC的结构和功能颇为重要。此外，URB1还参与调控pre-rRNA 3’末端ETS 区域（External transcribed spacer， ETS）折叠和加工。URB1在PDFC的定位参与了3’ETS的锚定、折叠与去除。URB1缺失导致3’ETS折叠异常，U8 snoRNA与pre-rRNA的结合受阻，导致3’ETS的加工异常。这些异常的pre-rRNA中间产物在核仁中大量累积，进而激活RNA稳态监控系统（RNA Exosome）在核仁发挥活性，引发异常pre-rRNA的降解，致使成熟的28S rRNA减少，无法维持细胞内核糖体的稳态和蛋白质合成，因而造成斑马鱼和小鼠的早期发育缺陷，甚至死亡。该工作利用超高分辨率生物成像、单分子RNA成像、RNA二级结构解析以及动物模型等多种研究手段，全面揭示了核仁精细结构与pre-rRNA的加工相互协同，共同维持核仁内微环境稳定，为认识核仁功能提供了全新见解。此外，该研究证明了URB1这类非流动性蛋白质在核仁液-液相分离环境中的关键组织作用，为探究三维pre-rRNA加工机制、核仁组装形成和功能提供了新思路。研究工作得到中科院、国家自然科学基金、科技部和上海市科学技术委员会等的资助，并获得分子细胞卓越中心细胞分析技术平台、斑马鱼技术平台、分子生物学技术平台和浙江大学良渚实验室的支持。