Deadenylation in Mammalian mRNA Turnover

描述（由申请人提供）：mRNA周转在基因表达中起重要作用。特定的细胞信号可以瞬时稳定不稳定的mRNA或使稳定的mRNA不稳定以调节蛋白质表达。 mRNA周转的失调与一系列人类疾病相关。两个重要的mRNA衰变过程是无义介导的衰变（NMD）和富含AU的元件（ARE）介导的衰变，无义介导的衰变（NMD）是检测和降解未能编码全长蛋白质的mRNA的过程，富含AU的元件（ARE）介导的衰变是导致具有战神的mRNA快速衰变的原因。这些通常在编码原癌基因、细胞因子和生长因子的mRNA的3'UTR中发现。这两种mRNA衰变途径都触发了快速的mRNA去腺苷化，这是mRNA衰变中的一个重要的调节步骤。为了了解mRNA衰变在基因表达和疾病中的调节方式，我们使用生物信息学方法鉴定了10种推定的人类去腺苷酸酶。将由下列人员研究这些问题：1）测试它们的体外去腺苷化活性，和2）通过研究它们在人组织培养细胞中无义介导的衰变和3）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.