STRUCTURE STUDIES OF TRANSCRIPTIONAL SILENCING

转录沉默是一种控制基因表达的表观遗传学机制。位于真核细胞染色体某些区域的基因被永久抑制。这种可遗传的转录沉默状态是由染色质结构改变引起的，这种结构可以从一代传到下一代。在从酵母到人类的各种生物中都观察到了基因沉默。沉默的例子包括分裂和发芽酵母中的交配型基因座，果蝇中的位置效应变异，以及哺乳动物中的X染色体失活。在酿酒酵母中，已知几种蛋白质复合体对在几个基因组座位上建立和维持转录沉默至关重要。它们包括沉默信息调节蛋白Sir1p、Sir2p、Sir3p和Sir4p，以及几种序列特异性DNA结合蛋白、起源识别复合体(ORC)、Rap1p和Abf1p。转录沉默的结构基础仍然知之甚少。我们将以X射线结晶学为主要手段研究SIR蛋白和ORC的结构和功能。这项研究的结果可能有助于理解表观遗传、DNA修复和衰老。

Transcriptional silencing is an epigenetic mechanism for control of gene expression. Genes located in certain regions of the eukaryotic chromosomes are permanently repressed. This heritable transcriptionally silent state is caused by altered chromatin structure that can be propagated from one generation to the next. Gene silencing has been observed in organisms ranging from yeast to human. Examples of silencing include mating-type loci in fission and budding yeasts, position effect variegation in Drosophila, and X-chromosome inactivation in mammals. In Saccharomyces cerevisiae, several protein complexes are known to be critical for establishing and maintaining transcriptional silencing at several genomic loci. They include the Silent Information Regulator proteins, Sir1p, Sir2p, Sir3p and Sir4p, and several sequence-specific DNA binding proteins, the Origin Recognition Complex (ORC), Rap1p and Abf1p. The structural basis of transcriptional silencing is still poorly understood. We will study the structure and function of the SIR proteins and ORC using X-ray crystallography as our principal method. The result of this study may facilitate an understanding of epigenetic inheritance, DNA repair and aging.