Elucidating the molecular basis for DNA primer synthesis

我们的细胞和来自所有生物体的细胞都含有DNA，即所谓的“生命的遗传蓝图”，它为我们所有的基因编码信息。DNA有一个简单的重复聚合结构，由两条互补的DNA链组成，这些DNA链由碱基组成，形成长串状的双螺旋结构，构成基因组。我们的基因组被打包成染色体，包含在几乎每个细胞的细胞核中。当细胞分裂产生子细胞时，这些信息必须被忠实地复制。细胞产生大量负责“复印”DNA蓝图的蛋白质。负责精确复制细胞遗传密码的蛋白质被称为DNA聚合酶。然而，聚合酶不能从头开始产生或复制DNA，需要合成一个短引物来复制大部分基因组DNA。幸运的是，所有细胞都有一种叫做DNA引物的引物酶，它的作用是制造这些起始引物，尽管它们是如何产生这些短聚合物的还不太清楚。在这个研究项目中，我们建议确定来自细菌和人类细胞的DNA引物如何能够完成引物合成的基本任务。这一建议将为所有细胞中DNA合成所必需的基本复制机制提供关键的见解。了解启动和维持有效DNA复制的启动机制将有助于发现治疗与不受控制的增殖相关的病症和疾病的新策略，如癌症和微生物感染。

Our cells and those from all living organisms contain DNA, the so called "genetic blueprint of life", that encodes the information for all our genes. DNA has a simple repeating polymeric structure composed of two complementary strands of DNA composed of bases, which form long, string-like, double-helical structures that make up the genome. Our genome is packaged away into chromosomes, contained within the nucleus of nearly every cell. This information must be faithfully copied as cells divide to produce daughter cells. Cells produce a large number of proteins responsible for "photocopying" this DNA blueprint. The proteins tasked with accurately copying the cell's genetic code are called DNA polymerases. However, polymerases are unable to produce or copy DNA from scratch and require the synthesis of a short primer from which to copy the bulk of the genomic DNA. Fortunately, all cells possess a priming enzyme called DNA primases, whose role it is to make these initiating primers, although how they produce these short polymers from is still poorly understood. In this research programme, we are proposing to determine how DNA primases, from bacteria and human cells, are able to perform the essential task of primer synthesis. This proposal will provide critical insights into this fundamental replicative mechanism that is essentially required for DNA synthesis in all cells. Understanding priming mechanisms that initiate and maintain efficient DNA replication will help uncover new strategies to treat conditions and diseases associated with uncontrolled proliferation, such as cancer and microbial infections.