Stochastic modelling chromosome replication

随机建模染色体复制

• 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

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.

所有的细胞都包含一个完整的生物体DNA拷贝，这是生命的遗传蓝图，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拷贝，因此在细胞分裂之前，染色体必须完全准确地复制。真核生物，如酵母和人类，拥有庞大的基因组，其中包含数百万个编码遗传信息的碱基。为了确保在允许的时间内完成这些基因组的复制，DNA复制过程从每条染色体沿着的多个位点开始，称为复制起点。这些复制起点是专门的DNA序列，组装细胞机器，然后沿着DNA阅读和复制遗传物质。细胞必须激活足够的复制起点，以确保染色体的完全复制。控制复制起点激活的重要性通过可能由不受控制的染色体复制引起的基因组不稳定性而突出。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复制过程中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，对确保遗传完整性的基础生物学的更好理解将提供新的见解，从而改善对这些疾病的诊断和治疗。我们想了解每条染色体上的多个复制起点是如何协调的，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，可以用来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括更复杂的场景。其中一种情况是当DNA复制过程遇到DNA损伤时会发生什么。这一点很重要，因为DNA的损伤会导致癌症等遗传疾病。此外，许多靶向癌细胞的药物（化疗）通过破坏DNA起作用，因为癌细胞比正常健康细胞更容易受到DNA损伤。通过结合数学建模和实验工作，我们的目标是确定染色体复制过程的优势和劣势，这可能是癌症等遗传疾病的基础。从长远来看，这项工作将有助于我们理解遗传疾病（包括癌症）的生物学基础，并可能导致新的治疗策略。

项目成果

A Link between ORC-origin binding mechanisms and origin activation time revealed in budding yeast.

• DOI: 10.1371/journal.pgen.1003798
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Hoggard T;Shor E;Müller CA;Nieduszynski CA;Fox CA
• 通讯作者: Fox CA

Optimal Placement of Origins for DNA Replication

DNA 复制起点的最佳放置

• DOI: 10.48550/arxiv.1202.0433
• 发表时间: 2012
• 作者: Karschau J

High quality de novo sequencing and assembly of the Saccharomyces arboricolus genome.

• DOI: 10.1186/1471-2164-14-69
• 发表时间: 2013-01-31
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Liti G;Nguyen Ba AN;Blythe M;Müller CA;Bergström A;Cubillos FA;Dafhnis-Calas F;Khoshraftar S;Malla S;Mehta N;Siow CC;Warringer J;Moses AM;Louis EJ;Nieduszynski CA
• 通讯作者: Nieduszynski CA

Optimal placement of origins for DNA replication.

• DOI: 10.1103/physrevlett.108.058101
• 发表时间: 2012-02-03
• 期刊: Physical review letters
• 影响因子: 8.6
• 作者: Karschau J;Blow JJ;de Moura AP
• 通讯作者: de Moura AP

The dynamics of genome replication using deep sequencing.

• DOI: 10.1093/nar/gkt878
• 发表时间: 2014-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Müller CA;Hawkins M;Retkute R;Malla S;Wilson R;Blythe MJ;Nakato R;Komata M;Shirahige K;de Moura AP;Nieduszynski CA
• 通讯作者: Nieduszynski CA