Deadenylation in Mammalian mRNA Turnover

描述(申请人提供)：信使核糖核酸周转在基因表达中起着重要作用。特定的细胞信号可以暂时稳定不稳定的mRNAs或破坏稳定的mRNAs的稳定性，从而调节蛋白质的表达。信使核糖核酸周转失控与一系列人类疾病有关。两个重要的mRNA衰变过程是无意义介导的衰变(NMD)和富含AU的元件(ARE)介导的衰变，前者是检测和降解不能编码全长蛋白质的mRNAs的过程，后者是导致具有ARs的mRNAs快速衰变的过程。它们通常存在于编码原癌基因、细胞因子和生长因子的mRNAs的3‘非编码区。这两条信使核糖核酸的衰变途径都触发了信使核糖核酸的快速去烯化，这通常是信使核糖核酸衰变的一个重要的调节步骤。为了了解基因表达和疾病中mRNA的衰退是如何调节的，我们用生物信息学的方法确定了10种假定的人类死烯基酶。这些研究将通过：1)测试它们的体外去烯化活性，2)研究它们在无意义介导的衰变中的作用，以及3)在人类组织培养细胞中研究它们在ARE介导的衰变中的作用。

DESCRIPTION (provided by applicant): mRNA turnover plays an essential role in gene expression. Specific cell signals can transiently stabilize unstable mRNAs or destabilize stable mRNAs to regulate protein expression. Misregulation of mRNA turnover is associated with a range of human diseases. Two important mRNA decay processes are those of nonsense-mediated decay (NMD), a process that detects and degrades mRNAs that fail to encode full-length protein, and AU-rich element (ARE)-mediated decay, which is responsible for the rapid decay of mRNAs with AREs. These are often found in the 3'UTR of mRNAs encoding proto-oncogenes, cytokines and growth factors. Both of these mRNA decay pathways trigger rapid mRNA deadenylation, an important often regulatory step in mRNA decay. With the long-term goal of understanding how mRNA decay is regulated in gene expression and disease, we have identified ten putative human deadenylases using a bioinformatics approach. These will be studied by: 1) testing their in vitro deadenylation activity, and 2) by studying their role in nonsense-mediated decay and in 3) ARE-mediated decay in human tissue culture cells.