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

组蛋白的供应和需求：刀刃上的生命

• 批准号: RGPIN-2019-05796
• 负责人: Verreault, Alain
• 金额: $ 4.94万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757504
• 关键词: Histone; protein; supply; demand; life

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.

DNA是一种聚合物，存在于每一种真核细胞类型中。DNA编码了确保细胞保持活力和正常运作所需的所有信息。在细胞中，DNA与被称为组蛋白的特殊包装蛋白密切相关，组蛋白将DNA组织成更紧凑的形式，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所有的DNA，而且还必须确保DNA不受损害。这是确保两个子代细胞继承其活性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，许多事件可能会出错，导致DNA损伤的积累。这些事件之一是组蛋白过量的存在，这是已知的干扰DNA修复的因素。因此，细胞进化出了复杂的分子机制，以确保可用的组蛋白蛋白的数量不超过正在合成的DNA的数量，并且需要包装成核小体。这些机制的确切性质，以及它们平衡组蛋白生产和DNA生产的方式，尚不清楚。这项研究计划的目标是利用面包师酵母中可用的强大工具来破译这一过程。面包酵母是生物学中常用的一种有机体。这将通过检验我们的工作假说来实现。在我们的假说中，一种名为HPC2的蛋白质充当了平衡组蛋白生产和DNA生产的“传感器”。HPC2已知能结合组蛋白并促进核小体的形成。使用酵母还将使我们能够进行一项强大的实验，即所谓的基因筛查，以识别在这一过程中发挥作用的其他基因。由于DNA和组蛋白在所有真核生物中形成核小体，破译酵母中的这种调控机制将有助于我们揭示一种有助于维持从不起眼的面包酵母到人类的大量物种的DNA序列完整性的机制。