Stochastic modelling chromosome replication

随机建模染色体复制

基本信息

批准号：
BB/G001596/1
负责人：
Conrad Nieduszynski
金额：
$ 69.14万
依托单位：
University of Nottingham
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG001596%2F1
关键词：
Stochastic modelling chromosome replication

项目摘要

All cells contain a complete copy of the organism's DNA, the genetic blueprint of life, packaged into discrete units called chromosomes. Since new cells need a copy of the genetic material, the chromosomes must be completely and accurately replicated before the cell can divide. Eukaryotes, such as yeast and humans, have large genomes with millions of bases encoding the genetic information. To ensure complete replication of these genomes within the allowed time, the process of DNA replication starts at multiple sites along each chromosome, called replication origins. These replication origins are specialised DNA sequences that assemble the cellular machinery that then moves along the DNA reading and copying the genetic material. It is essential that the cell activates sufficient replication origins to ensure complete replication of the chromosomes. The importance of controlling replication origin activation is highlighted by the genome instability that may result from uncontrolled chromosome replication. Despite the importance of DNA replication origins we understand little about the DNA sequences that specify and control them. Failures in the processes of DNA replication lead to genetic instability and diseases such as cancer and congenital disorders. We hope that a better understanding of the basic biology that ensures genetic integrity will give new insights that will allow improved diagnosis and treatment of these diseases. We want to understand how the multiple replication origins on each chromosome are coordinated to ensure that the chromosome is successfully replicated. To study this 'system' we have developed a mathematical model that can be used to simulate the behaviour of all the replication origins on a chromosome. Now we will use our mathematical model to make predictions about chromosome replication that we can test experimentally in the lab. This will allow us to improve the model and include more complex scenarios. One such scenario is what happens when the DNA replication process encounters damage to the DNA. This is important, as damage to the DNA gives rise to genetic diseases such as cancer. Furthermore, many drugs that target cancer cells (chemotherapy) work by damaging the DNA, since cancer cells are more vulnerable to DNA damage than normal healthy cells. By combining mathematical modelling and experimental work we aim to identify the strengths and weaknesses of the chromosome replication process that may underlie genetic diseases such as cancer. In the long-term this work will help in our understanding of the biological basis of genetic diseases, including cancer, and may lead to new therapeutic strategies.

所有细胞都包含生物体 DNA（生命的遗传蓝图）的完整副本，被包装成称为染色体的离散单元。由于新细胞需要遗传物质的副本，因此在细胞分裂之前染色体必须完整且准确地复制。真核生物，例如酵母和人类，拥有庞大的基因组，其中有数百万个编码遗传信息的碱基。为了确保这些基因组在允许的时间内完成复制，DNA 复制过程从每条染色体上的多个位点开始，这些位点称为复制起点。这些复制起点是专门的 DNA 序列，它们组装细胞机器，然后沿着 DNA 移动，读取和复制遗传物质。细胞激活足够的复制起点以确保染色体的完全复制至关重要。不受控制的染色体复制可能导致基因组不稳定，凸显了控制复制起点激活的重要性。尽管 DNA 复制起点很重要，但我们对指定和控制它们的 DNA 序列知之甚少。 DNA 复制过程的失败会导致遗传不稳定以及癌症和先天性疾病等疾病。我们希望更好地了解确保遗传完整性的基础生物学将提供新的见解，从而改进这些疾病的诊断和治疗。我们想要了解每条染色体上的多个复制起点如何协调以确保染色体成功复制。为了研究这个“系统”，我们开发了一个数学模型，可用于模拟染色体上所有复制起点的行为。现在我们将使用我们的数学模型来预测染色体复制，我们可以在实验室中进行实验测试。这将使我们能够改进模型并包含更复杂的场景。其中一种情况是当 DNA 复制过程遇到 DNA 损伤时会发生这种情况。这很重要，因为 DNA 损伤会导致癌症等遗传疾病。此外，许多针对癌细胞的药物（化疗）通过破坏 DNA 发挥作用，因为癌细胞比正常健康细胞更容易受到 DNA 损伤。通过结合数学模型和实验工作，我们的目标是确定可能导致癌症等遗传疾病的染色体复制过程的优点和缺点。从长远来看，这项工作将有助于我们了解包括癌症在内的遗传疾病的生物学基础，并可能带来新的治疗策略。