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.

所有细胞均包含生物体DNA的完整副本，即生命的遗传蓝图，被包装成被称为染色体的离散单元。由于新细胞需要遗传物质的副本，因此必须在细胞分裂之前完全准确地复制染色体。诸如酵母和人类等真核生物具有大型基因组，数百万碱基编码遗传信息。为了确保在允许时间内完全复制这些基因组，DNA复制过程沿每个染色体的多个位点开始，称为复制起源。这些复制起源是专门的DNA序列，这些序列组装了然后沿着DNA移动的细胞机制，读取和复制遗传物质。细胞必须激活足够的复制起源以确保染色体的完全复制。控制复制起源激活的重要性是由基因组不稳定性和可能由不受控制的染色体复制引起的疾病突出的。尽管DNA复制起源很重要，但我们对指定和控制它们的DNA序列了解甚少。 DNA复制过程中的失败导致遗传不稳定和癌症和先天性疾病等疾病。将来，对确保遗传完整性的基本生物学有更好的理解将提供新的见解，从而可以改善对这些疾病的诊断和治疗。我们旨在了解如何控制复制起源激活时间。为了研究这一过程，我们比较了不同生物体中的基因组复制。我们主要与贝克的酵母合作，因为这是安全，便宜和道德的，但是最重要的是，贝克的酵母和人之间的所有基因组复制步骤都相似。因此，我们使我们与酵母一起工作的进步将为以后的研究和对待人的治疗提供丰富的信息。最近，我们发现在不同的酵母菌中，基因组复制的模式非常相似（用相当于比较鸟类的人的进化术语）。这些比较使我们能够发现个体复制起源，这些复制起源显示出酵母菌物种之间活动差异的巨大差异。现在，我们将研究两种物种之间存在起源激活时间差异的原因。我们的实验表明，接近原点的DNA“调节”序列是造成的。现在，我们想找到这些序列，并确定它们如何改变复制起源的激活时间。酵母中的基因组复制与人们之间的相似性意味着在酵母中发现这些调节序列的发现可能会使人们在人们中如何调节复制起源的激活时间。如果复制起源太少，那么基因组的一部分将无法复制，这可能导致癌症和发育疾病。因此，将来，更好地理解复制起源如何受到调节可能会允许为这些疾病提供改进的治疗方法。

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

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

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