Mechanisms Regulating Genome Replication

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，拥有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移动，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复制过程中的失败导致遗传不稳定和疾病，如癌症和先天性疾病。在未来，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，这将有助于改善这些疾病的诊断和治疗。我们的目标是了解复制起点激活时间是如何控制的。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。首先，我们使用面包酵母，因为这是安全的，便宜的和道德的，但最重要的是，所有的基因组复制的步骤面包酵母和人之间是相似的。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（从进化的角度来看，相当于将人与鸟类进行比较）。这些比较使我们能够发现单个复制起点，这些复制起点在酵母物种之间的活性存在显着差异。现在，我们将研究是什么原因导致了这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”序列负责。现在我们想找到这些序列，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的相似性意味着在酵母中发现这些调控序列可能对人类复制起点激活时间的调控提供信息。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疾病。因此，在未来，更好地了解复制起点激活时间是如何调节的，可能会允许开发这些疾病的改进治疗方法。

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.