Characterising scaffold attachment factor B1 as a novel regulator of dicer function

人体内的每个细胞都有一个含有带状染色体的核，这些染色体含有基因，这些基因共同保存着关于身体的每一条信息。每个DNA基因都被翻译成信使RNA，用来产生一种独特的蛋白质。这些蛋白质表达的改变可能导致疾病。直到最近，科学家们还认为，基因表达水平是通过调节DNA和蛋白质的相互作用来控制的。然而，在过去的5-10年里，一组被称为microRNAs的全新基因被发现，并被发现调节信使RNA的表达。这些内源性miRNA通过抑制mRNAs向蛋白质的转化，介导了一个全新的基因调控水平。这些发现的意义令人震惊，因为它预测，对于许多生物过程，如果不是所有的生物过程，到目前为止还存在着一种未知的控制水平。最近的研究证实，miRNAs确实参与了许多基本的生化和细胞通路的调节，如干细胞更新和分化、癌症和细胞凋亡、细胞应激反应和记忆功能。此外，据预测，多达三分之一的人类基因可能受microRNAs调控。MicroRNAs的生产和功能有两个关键阶段：第一个阶段发生在细胞核中，涉及将大的初级miRNA转录本切割成较小的前体microRNA，然后将其输出到细胞质；第二阶段涉及将前体microRNA(由一种名为DICER的酶)切割成较小的片段，然后该片段可以找到其目标mRNA并使其沉默。控制这些过程的一些因素是已知的，但另一些因素已被预测存在。我们发现一种名为支架附着因子B1(SAFB1)的蛋白质参与了microRNAs从细胞核到细胞质的运动，并在那里与microRNA加工酶Disher结合。我们的发现还表明，SAFB1可能在应激过程中控制microRNAs的成熟方面特别重要。我们建议进行一系列研究，以调查SAFB1是否改变了DICER对前体microRNAs的处理，以及microRNA介导的信使RNA沉默是否发生了改变。这些发现的意义是重要的，因为它们代表了一种全新的、以前未知的蛋白质类别，参与了microRNA功能的调节，从而参与了基因调节。这些发现的意义将进一步加深我们对身体如何工作并在健康和疾病期间调节基因表达的理解。

Every cell within the body has a nucleus containing ribbon-like chromosomes that contain genes and collectively these genes hold every piece of information about the body. Each DNA gene is translated into a messenger RNA that is used to produce a unique protein. Alterations in the expression of these proteins may result in disease. Until recently scientists believed that the level of gene expression was controlled by regulating DNA and protein interactions. However, in the last 5-10 years a totally new group of genes termed the microRNAs were discovered and found to regulate the expression of messenger RNAs. These endogenous miRNA mediate an entirely new level of gene regulation by inhibiting the conversion of mRNAs to protein. The implications of these findings were startling as it predicted that there was a hitherto unknown level of control for many if not all biological processes. Recent studies have confirmed that miRNAs are indeed involved in the regulation of many fundamental biochemical and cellular pathways, e.g. stem cell renewal and differentiation, cancer and apoptosis, cell stress responses and memory function. Furthermore, it is predicted that as many one third of all human genes may be regulated by microRNAs. There are two key stages in the production and function of microRNAs; the first occurs in the nucleus of cells and involves the cutting of large primary miRNA transcripts into smaller precursor microRNAs that are then exported to the cytoplasm; the second stage in the cytoplasm of the cell involves the cutting of the precursor microRNA (by an enzyme called Dicer) into a smaller fragment that can then find its target mRNA and silence it. Some of the factors controlling these processes are known, however others have been predicted to exist. We have found a protein called scaffold attachment factor B1 (SAFB1) is involved in the movement of microRNAs from the nucleus to the cytoplasm and that there it binds the microRNA processing enzyme Dicer. Our findings also suggest that SAFB1 may be particularly important in controlling the maturation of microRNAs during stress. We propose to carry out a number of studies to investigate whether SAFB1 alters the processing of precursor microRNAs by Dicer and to see if microRNA mediated silencing of messenger RNA is altered. The implications of these findings are important because they represent: an entirely new previously unknown class of protein being involved in the regulation of microRNA function and therefore gene regulation. The implications of the findings will further our understanding of how the body works and regulates the expression of genes during health and disease.