Structural and functional characterization of a mammalian chromatin remodeling ATPase

我们身体每个细胞中的DNA被压缩20，000倍，形成一个紧凑，高度有序的结构，称为染色质，使其能够适应微小的细胞核。这种压缩是由蛋白质复合物实现的，称为组蛋白，它将DNA缠绕在自己周围形成更高级的结构。然而，这种紧密的包装对于在复制和修复的基本过程中需要获得DNA的因素来说是一个障碍。为了解决这个问题，细胞使用非常专门的多蛋白质组装，称为染色质重塑复合物。这些复合物不仅需要定位正确的DNA片段，而且一旦找到它，它们还需要沿着线轴沿着DNA串并解开它。这项工作需要能量，这就是为什么这些复合物也被称为分子马达并在此过程中消耗能量的原因。由于它们的重要作用，当这些复合物的成分缺失或突变时，细胞失去适当控制其命运和生长的能力。越来越多的证据表明，ATP依赖性染色质重塑复合物的功能障碍导致高度损害性的遗传疾病（α-地中海贫血X连锁智力低下综合征，X连锁Rett综合征，Cocakyne综合征，Schimke免疫骨发育不良，Rubinstein-Taybi综合征，Coffin-Lowry综合征等）。和各种癌症。我在牛津大学威康信托人类遗传学中心的研究小组与赫尔辛基大学的罗曼·图马博士合作，对染色质重塑复合物如何工作以及它们的活性如何调节和控制基因的基本问题感兴趣。我希望使用两种技术，即X射线晶体学和电子显微镜，它们可以让你看到非常小的物体的惊人细节，更近距离地观察这些染色质重塑复合物的形状。该项目的成果是提供原子水平的快照，显示染色质重塑复合物如何在细胞内执行其非常重要的任务。

The DNA in every cell of our body is compressed 20,000 times in length into a compact, highly ordered structure called chromatin, enabling it to fit into the tiny cell nucleus. This compression is achieved by protein complexes, called histones, which spool the DNA around themselves into higher order structures. However, this tight packaging is a barrier to factors that need to gain access to the DNA during the fundamental processes of replication and repair. To solve this problem cells use very specialized multi-protein assemblies called chromatin remodeling complexes. These complexes not only need to locate the right piece of DNA that is to be made accessible, but once they find it, they also need to slide the DNA string along the spools and unravel it. This work requires energy, which is the reason why these complexes are also called molecular motors and burn energy in the process.Because of their important role, when components of these complexes are absent or mutated, cells lose the ability to properly control their fates and growth. Accumulating evidence suggests that malfunctioning ATP-dependent chromatin remodeling complexes cause highly imparing genetic diseases (Alpha-thalassemia X-linked mental retardation syndrome, X-linked Rett syndrome, Cocakyne syndrome, Schimke immuno-osseous dysplasia, Rubinstein-Taybi syndrome, Coffin-Lowry syndrome, etc.) and various types of cancer. My group at the Wellcome Trust Centre for Human Genetics (Oxford), in collaboration with Dr. Roman Tuma at the University of Helsinki, is interested in the fundamental question of how chromatin remodeling complexes work and how their activity regulates and controls genes. I am hoping to use two techniques called X-ray crystallography and electron microscopy, which allow you to look with amazing details at very small objects, to have a closer look at the shape of these chromatin remodeling complexes. The outcome of this project is to provide snapshots at atomic level that show how chromatin remodeling complexes perform their very important task within the cell.