Structural and functional characterization of a mammalian chromatin remodeling ATPase

我们身体每个细胞中的DNA被压缩2万倍，形成一种紧凑、高度有序的结构，称为染色质，使其能够适应微小的细胞核。这种压缩是通过蛋白质复合体实现的，这种复合体被称为组蛋白，它将自己周围的DNA卷曲成更高顺序的结构。然而，这种紧密的包装是在复制和修复的基本过程中需要获得DNA的因素的障碍。为了解决这个问题，细胞使用非常特殊的多蛋白质组件，称为染色质重塑复合体。这些复合体不仅需要找到要访问的正确DNA片段，而且一旦找到，它们还需要沿着线轴滑动DNA线并解开它。这项工作需要能量，这就是为什么这些络合物也被称为分子马达，并在这个过程中消耗能量。由于它们的重要作用，当这些络合物的成分缺失或突变时，细胞就会失去适当控制自己命运和生长的能力。越来越多的证据表明，功能异常的ATP依赖的染色质重塑复合体会导致高度遗传的疾病(阿尔法-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免疫性骨发育不良、Rubinstein-Taybi综合征、Coffin-Lowry综合征等)。以及各种癌症。我在牛津大学惠康信托人类遗传学中心的团队与赫尔辛基大学的罗曼·图马博士合作，对染色质重塑复合体如何工作以及它们的活动如何调节和控制基因这一基本问题感兴趣。我希望使用两种技术，即X射线结晶学和电子显微镜，这两种技术可以让你在非常小的物体上看到令人惊叹的细节，以更仔细地观察这些染色质重塑复合体的形状。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体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.