Histone protein supply and demand: life on a knife's edge

DNA是一种聚合物，存在于每一种真核细胞类型中。DNA编码所有必要的信息，以确保细胞保持活力和正常运作。在细胞中，DNA与被称为组蛋白的特殊包装蛋白紧密相关，组蛋白将DNA组织成一种更紧密的形式，称为核小体。为了分裂成两个子细胞，一个细胞不仅必须忠实地复制它所有的DNA，而且还必须确保DNA没有受损。这是确保两个子细胞继承其生存能力和正常功能所需的正确DNA序列的关键要求。在DNA复制过程中，许多事件可能出错并导致DNA损伤的积累。这些事件之一是过量的组蛋白的存在，这是已知的干扰DNA修复。因此，细胞已经进化出复杂的分子机制，以确保可用组蛋白的数量不会超过正在合成并需要包装到核小体中的DNA的数量。这些机制的确切性质，以及它们如何平衡组蛋白的产生和DNA的产生，目前还不清楚。这项研究计划的目标是利用面包师酵母（生物学中常用的一种有机体）中可用的强大工具，来破译这是如何工作的。这将通过测试我们的工作假设来完成，其中一种名为Hpc2的蛋白质，已知可以结合组蛋白并促进核小体的形成，作为平衡组蛋白产生和DNA产生的“传感器”。使用酵母还将使我们能够进行一项强大的实验，即基因筛选，以识别在此过程中起作用的其他基因。因为DNA和组蛋白在所有真核生物中都形成核小体，破译酵母中的这种调节机制将有助于我们阐明一种机制，这种机制有助于维持从不起眼的面包酵母到人类的大量物种的DNA序列完整性。

DNA is a polymer that is found in every eukaryotic cell type. DNA encodes all the information necessary to ensure that the cell remains alive and functions properly. In cells, DNA is tightly associated with specialized packaging proteins, known as histones, that organize DNA into a more compact form called the nucleosome. In order to divide into two daughter cells, a cell must not only faithfully duplicate all its DNA, but it also has to make sure that the DNA is free of damage. This is a crucial requirement to ensure that the two daughter cells inherit the correct DNA sequences needed for their viability and proper function. During DNA duplication, many events can go wrong and lead to the accumulation of DNA damage. One of these events is the presence of an excess of histone proteins, which is known to interfere with DNA repair. Accordingly, cells have evolved sophisticated molecular mechanisms to ensure that the amounts of available histone proteins do not exceed the amount of DNA that is being synthesized and needs to be packaged into nucleosomes. The precise nature of these mechanisms, and the way by which they operate to balance histone production and DNA production, is not known. The goal of this research program is to take advantage of the powerful tools available in the baker's yeast, an organism commonly used in biology, to decipher how this works. This will be done by testing our working hypothesis in which a protein called Hpc2, which is known to bind histones and promote the formation nucleosomes , acts as a "sensor" to balance histone production and DNA production. Using yeast will also enable us to perform a powerful experiment, known as a genetic screen, to identify other genes that function in this process. Because DNA and histones form nucleosomes in all eukaryotic organisms, deciphering this regulatory mechanism in yeast will help us shed light into a mechanism that contributes to maintain DNA sequence integrity in a vast number of species that range from the humble baker's yeast all the way to humans.