Regulation of Mammalian mRNA Decay

哺乳动物 mRNA 衰变的调控

• 批准号: 10387387
• 负责人: MEGERDITCH KILEDJIAN
• 金额: $ 5.56万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387387
• 关键词: Address; Adenine; Cells; DNA; Diphosphates; Disease; Elements; Enzymes; Flavins; Funding; Gene Expression; Genetic Transcription; Grant; Guanosine; Homeostasis; Hydrolase; In Vitro; Link; Malignant Neoplasms; Messenger RNA; Minor; Molecular; Nicotinamide adenine dinucleotide; Nucleotides; Oxidation-Reduction; Post-Transcriptional Regulation; Proteins; Proto-Oncogenes; RNA; RNA Caps; RNA Decay; RNA metabolism; Regulation; Role; Stress; Translations; Work; clinical phenotype; cofactor; genetic information; insight; mRNA Decay; mRNA Stability; novel

Summary of the funded parental grant GM067005: The control of mRNA stability is a critical determinant in the post-transcriptional regulation of eukaryotic gene expression. Even minor alterations in mRNA stability can have profound consequences and may manifest as clinical phenotypes as illustrated by the ability of aberrantly expressed proto-oncogenes that can give rise to malignancies. Eukaryotic mRNAs are generally thought to possess an N7 methyl guanosine (m7G) cap at their 5¢ end to promote their stability and translation. However, our recent demonstration that mammalian mRNAs can also carry a 5´-end nicotinamide adenine dinucleotide (NAD) cap that in contrast to the m7G cap promotes mRNA decay, provides a new paradigm for mRNA 5´ end processing and the contribution of nucleotide metabolites in mRNA turnover. We now demonstrate that the redox state of NAD can also modulate 3´ RNA decay with free NAD functioning as a cofactor to enhance RNA decay and potentially providing a link to cellular energetics. Moreover, flavin adenine diphosphate (FAD) can also serve as a 5´ cap on mammalian RNAs with Nudt16 and DXO hydrolases functioning as proteins that can remove the FAD cap (deFADding) in vitro. We will build on these novel findings throughout this proposal within three specific aims. The first will address the functional role of free NAD on the control of 3´ end RNA decay in vitro and delineate the molecular mechanism involved in its stimulation of decay. The second will deduce changes in mRNA decay as a consequence of altered NAD levels in cells and assess the regulatory role imparted by stress conditions in modulating RNA decay through the control of NAD levels. In the last aim, we establish FAD cap as an alternative RNA cap, identify FAD-capped RNAs and decipher the role of FAD caps and the deFADding enzymes in cells. Collectively, the proposed studies will provide insight into a heretofore unknown fundamental post-transcriptional regulatory mechanism and will provide the framework for potential novel avenues to control gene expression in normal and disease states.

资助父母补助金GM 067005摘要： mRNA稳定性的控制是转录后调控的关键因素 真核生物基因表达。即使是mRNA稳定性的微小改变， 深刻的后果，并可能表现为临床表型，如由 异常表达的原癌基因的能力，可以引起恶性肿瘤。 真核生物的mRNA通常被认为具有N7甲基鸟苷（m7G）帽 在它们的5美分末端，以促进它们的稳定性和翻译。然而，我们最近 证明哺乳动物mRNAs也可以携带5 ′端烟酰胺腺嘌呤， 与m7G帽相反，m7G帽促进mRNA衰变，提供了 mRNA 5 ′端加工的新范式和核苷酸的贡献 代谢产物的mRNA周转。我们现在证明，NAD的氧化还原状态也可以 调节3 ′ RNA衰变，游离NAD作为辅助因子发挥作用，以增强RNA衰变 并可能提供与细胞能量学的联系。此外，黄素腺嘌呤 二磷酸（FAD）也可以作为哺乳动物RNA上的5 ′帽，具有Nudt16， DXO水解酶作为蛋白质起作用，可以去除FAD帽（deFADding）， 体外我们将在三个具体的范围内，在整个提案中建立这些新的发现 目标。第一部分将讨论游离NAD在3 ′端RNA控制中的功能作用 在体外衰变，并描绘其刺激衰变的分子机制。 第二个将推断mRNA衰减的变化是NAD水平改变的结果 并评估应激条件在调节RNA中赋予的调节作用 通过控制NAD水平来衰变。在最后一个目标中，我们建立了FAD上限， 替代RNA帽，鉴定FAD帽RNA并破译FAD帽的作用， 细胞中的去脂肪酶。总的来说，拟议的研究将提供洞察力， 转化为迄今未知的基本转录后调节机制， 将为潜在的新途径提供框架，以控制基因表达， 正常和疾病状态。

项目成果

The RNA binding protein HuR determines the differential translation of autism-associated FoxP subfamily members in the developing neocortex.

• DOI: 10.1038/srep28998
• 发表时间: 2016-07-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Popovitchenko T;Thompson K;Viljetic B;Jiao X;Kontonyiannis DL;Kiledjian M;Hart RP;Rasin MR
• 通讯作者: Rasin MR

BAY11 enhances OCT4 synthetic mRNA expression in adult human skin cells.

• DOI: 10.1186/scrt163
• 发表时间: 2013-02-06
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Awe JP;Crespo AV;Li Y;Kiledjian M;Byrne JA
• 通讯作者: Byrne JA

5' End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA Decay through DXO-Mediated deNADding.

• DOI: 10.1016/j.cell.2017.02.019
• 发表时间: 2017-03-09
• 期刊: Cell
• 影响因子: 64.5
• 作者: Jiao X;Doamekpor SK;Bird JG;Nickels BE;Tong L;Hart RP;Kiledjian M
• 通讯作者: Kiledjian M

DcpS as a therapeutic target for spinal muscular atrophy.

• DOI: 10.1021/cb800120t
• 发表时间: 2008-11-21
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Singh J;Salcius M;Liu SW;Staker BL;Mishra R;Thurmond J;Michaud G;Mattoon DR;Printen J;Christensen J;Bjornsson JM;Pollok BA;Kiledjian M;Stewart L;Jarecki J;Gurney ME
• 通讯作者: Gurney ME

Structure and function of pre-mRNA 5'-end capping quality control and 3'-end processing.

• DOI: 10.1021/bi401715v
• 发表时间: 2014-04-01
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Jurado AR;Tan D;Jiao X;Kiledjian M;Tong L
• 通讯作者: Tong L