Mechanisms Regulating Genome Replication

调节基因组复制的机制

• 批准号: BB/K007211/2
• 负责人: Conrad Nieduszynski
• 金额: $ 29.43万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK007211%2F2
• 关键词: Mechanisms; Regulating; Genome; 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 people, 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 and diseases 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. In the future, 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 aim to understand how replication origin activation time is controlled. To study this process we have compared genome replication in different organisms. Primarily we work with baker's yeast, since this is safe, cheap and ethical, but most importantly all the steps of genome replication are similar between baker's yeast and people. Therefore advances we make working with yeasts will be informative for future studies and treatment of people. Recently we have found that the patterns of genome replication are very similar in different yeast species (in evolutionary terms equivalent to comparing people with birds). These comparisons allowed us to discover individual replication origins that show dramatic differences in activity between the yeast species. Now we will investigate what is responsible for this difference in origin activation time between the two species. Our experiments suggest that DNA 'regulatory' sequences close to the origin are responsible. Now we want to find these sequences and determine how they alter the activation time of the replication origin.The similarities between genome replication in yeast and people mean that the discovery of these regulatory sequences in yeast may be informative about how replication origin activation time is regulated in people. If too few replication origins activate, parts of the genome will fail to replicate and this can result in cancer and developmental diseases. Therefore, in the future, a better understanding of how replication origin activation time is regulated may allow the development of improved treatments for these diseases.

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。基因组不稳定和不受控制的染色体复制可能导致的疾病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。将来，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。我们的目标是了解如何控制复制起点激活时间。为了研究这个过程，我们比较了不同生物体中的基因组复制。我们主要使用面包酵母，因为它安全、便宜且合乎道德，但最重要的是，面包酵母和人类之间基因组复制的所有步骤都是相似的。因此，我们在酵母方面取得的进展将为未来的研究和人类治疗提供信息。最近我们发现不同酵母物种的基因组复制模式非常相似（从进化的角度来说，相当于将人与鸟类进行比较）。这些比较使我们能够发现个体复制起点，这些起点显示出酵母物种之间活性的巨大差异。现在我们将研究是什么导致了两个物种之间起源激活时间的差异。我们的实验表明，靠近起源的 DNA“调节”序列是造成这一现象的原因。现在我们想要找到这些序列并确定它们如何改变复制起点的激活时间。酵母和人类基因组复制之间的相似性意味着酵母中这些调控序列的发现可能会为人类如何调控复制起点激活时间提供信息。如果激活的复制起点太少，部分基因组将无法复制，这可能导致癌症和发育性疾病。因此，将来，更好地了解复制起点激活时间的调节方式可能有助于开发针对这些疾病的改进治疗方法。

项目成果

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

DNA replication timing influences gene expression level.

• DOI: 10.1083/jcb.201701061
• 发表时间: 2017-07-03
• 期刊: The Journal of cell biology
• 作者: Müller CA;Nieduszynski CA
• 通讯作者: Nieduszynski CA

Evolution of Genome Architecture in Archaea: Spontaneous Generation of a New Chromosome in Haloferax volcanii.

• DOI: 10.1093/molbev/msy075
• 发表时间: 2018-08-01
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Ausiannikava D;Mitchell L;Marriott H;Smith V;Hawkins M;Makarova KS;Koonin EV;Nieduszynski CA;Allers T
• 通讯作者: Allers T

A global profile of replicative polymerase usage.

• DOI: 10.1038/nsmb.2962
• 发表时间: 2015-03
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: Daigaku Y;Keszthelyi A;Müller CA;Miyabe I;Brooks T;Retkute R;Hubank M;Nieduszynski CA;Carr AM
• 通讯作者: Carr AM

Discovery of an unconventional centromere in budding yeast redefines evolution of point centromeres.

• DOI: 10.1016/j.cub.2015.06.023
• 发表时间: 2015-08-03
• 期刊: Current biology : CB
• 作者: Kobayashi N;Suzuki Y;Schoenfeld LW;Müller CA;Nieduszynski C;Wolfe KH;Tanaka TU
• 通讯作者: Tanaka TU