Mechanisms that underpin chromosome stability

自然界中最令人惊叹的工程成就之一是如何将超过2米的遗传物质（DNA）压缩并挤压近一百万次以适应人类细胞。实现这一目标的非凡结构是染色体。多细胞生物生存的根本是染色体在整个生物体的生命中得到稳定的维持。例如，维持染色体稳定性的缺陷可能导致非整倍体（染色体数量异常的细胞），这是许多形式的癌症所表现出的特征。这种产生染色体的基因组DNA的包装是通过复杂的折叠方案实现的。在第一级，DNA首先包裹在蛋白质混合物（称为组蛋白）周围，形成一个称为核小体的完整单元。每个人类细胞需要大约3000万个这样的积木来压缩我们的DNA。更高，更复杂的组织水平存在，其中核小体的线性阵列折叠到不同程度，形成不同的功能和结构域。重要的是，特殊的染色体结构域，如端粒和着丝粒，被组装起来，分别保持染色体末端的稳定，并使染色体在每次细胞分裂和生长时都能自我复制。染色体是如何分成这些不同的区室的仍然是个谜。这项研究将表明，决定染色体如何组织成稳定结构域的关键细胞机制是通过用称为变体的特殊形式的组蛋白替代组蛋白来改变染色体结构域的组成。这些组蛋白变体控制着核小体线性排列折叠成复杂的三维结构以执行特定功能的方式。这项基础研究将为染色体在癌症中如何变得不稳定提供重要的新信息。这也将使稳定染色体的新策略得以探索。

One of the most amazing engineering achievements in nature is how over 2 meters of genetic material (DNA) can be compacted and squeezed nearly a million times to fit into a human cell. The remarkable structure that achieves this is the chromosome. Fundamental to the survival of a multicellular organism is that the chromosome is stably maintained throughout out the life of an organism. For example, defects in maintaining chromosome stability can lead to aneuploidy (cells with an abnormal number of chromosomes), a feature exhibited by many forms of cancer. This packaging of genomic DNA that produces a chromosome is achieved by a complex scheme of folding. At the first level, DNA is first wrapped around a mixture of proteins (called histones) to form a complete unit known as a nucleosome. About 30 million of these building blocks are required in every human cell to compact our DNA. Higher, more complicated levels of organization exist in which a linear array of nucleosomes fold to various extents to form distinct functional and structural domains. Importantly, specialised chromosomal domains, like the telomere and centromere, are assembled that keep the ends of the chromosomes stable and enable a chromosome to copy itself every time our cells divide and grow, respectively. How a chromosome is divided into these different compartments remains a mystery. This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . These histone variants control the way a linear array of nucleosomes fold into complex three-dimensional structures to perform a specialised function. This fundamental research will provide important new information on how chromosomes become unstable in cancer. It will also enable new strategies, which stabilise the chromosome, to be explored.