Regulation of Mammalian mRNA Decay

哺乳动物 mRNA 衰变的调控

基本信息

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
项目类别：
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

项目摘要

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.

资助的父母赠款GM067005的摘要： mRNA稳定性的控制是转录后调节中的关键决定因素真核基因表达。深刻的后果，可能表现为临床表型表型，如你所示异常表达的原始浓缩的能力，可能引起恶性肿瘤。通常认为真核mRNA被认为折腾和N7甲基鸟嘌呤（M7G）帽但是，他们的稳定性和翻译为5¢ 演示Mamalian mamalian mRNA也可以携带5´-End Nicotinamide腺嘌呤与M7G盖相反的二核苷酸（NAD）盖促进了mRNA衰变，可提供 mRNA 5´末端加工的新范式和核苷酸的贡献 mRNA周转中的代谢物。自由nAD作为辅因子的自由NAD的模块化3´RNA衰减，以增强RNA衰减并可能提供与细胞能量的联系双磷酸盐（FAD）也可以用作NUDT16和NUDT16的Mamalian RNA上的5´盖 DXO水解酶作为蛋白质的作用，可以在体外。目标。体外衰减并描绘出所涉及的分子机制是衰减的刺激。由于NAD水平改变而导致mRNA衰减的第二个愿意变化在细胞和评估中，应力条件在调节RNA中赋予的规律性作用通过对NAD级别的控制衰减。替代RNA盖，识别fad限制的RNA并破译时尚帽的作用和细胞中的剥削酶。进入迄今未知的基本转录后调节机制和将为潜在的新型途径提供控制基因表达的框架正常和疾病状态。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

DcpS, a general modulator of cap-binding protein-dependent processes?

DOI：
10.4161/rna.7161
发表时间：
2008-10-01
期刊：
RNA BIOLOGY
影响因子：
4.1
作者：
Bail, Sophie;Kiledjian, Megerditch
通讯作者：
Kiledjian, Megerditch

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