Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells

我们的细胞含有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有一个简单的重复结构，由两条互补的DNA链组成，形成长串状的双螺旋结构，构成了基因组。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，染色体必须被复制。细胞产生大量负责“复印”DNA蓝图的蛋白质。负责精确复制我们遗传密码几十亿个字母的蛋白质被称为DNA复制聚合酶。在这个复制过程中，复制机制经常被受损的DNA停止，这可能导致复制失败或DNA序列突变的产生，最终导致疾病状态的发展，如癌症。幸运的是，我们的细胞产生损伤耐受蛋白，它的作用是防止这种情况发生，或者在复制停止时重新开始。我们最近在人类细胞中发现了一种名为PrimPol的新型人类病变绕过聚合酶，并表明这种蛋白质与其他细胞因子一起，在帮助细胞复制机制绕过每一轮细胞分裂过程中遇到的DNA损伤方面发挥着重要作用，从而确保有效的基因组复制。特别是，我们已经证明PrimPol的缺失会导致复制减慢，特别是过去由紫外线产生的病变，这表明它是通过这些DNA损伤进行有效复制所必需的。在这个项目中，我们建议确定这些分子机器如何能够绕过DNA损伤，该基因缺失或突变（例如疾病关联）的细胞和生物体后果是什么，最后，PrimPol如何与其他绕过蛋白合作，以确保复制以忠实和完整的方式进行。突变的积累会导致不受控制的细胞生长，从而导致癌症等疾病的发展。因此，了解当复制机制在损伤位点停止时细胞如何反应是很重要的。癌细胞的“阿喀琉斯之踵”是它们比我们体内的其他细胞生长得更快，因此它们更频繁地复制自己的DNA。正因为如此，许多癌症治疗故意引入损伤DNA复制，以选择性地减缓/杀死癌细胞。我们希望，通过了解复制机制是如何耐受这种损伤的，我们也许能够找到方法，使癌细胞更有可能被阻断DNA复制的药物杀死，从而提高癌症治疗的效率。

Our cells contain DNA, the so called "genetic blueprint of life", which encodes the information for all our genes. DNA has a simple repeating structure composed of two complementary strands of DNA, which form long, string-like, double-helix structures that make up the genome. Our genome is packaged away into chromosomes, contained in the nucleus of nearly every cell, which must be 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 several billion letters of our genetic code are called DNA replication polymerases. During this copying process the replication machinery is frequently stopped by damaged DNA and this can lead to failure to replicate or the production of mutations to the sequence of the DNA that can, eventually, lead to the development of disease states, such as cancer. Fortunately, our cells produce damage tolerance proteins whose role it is to prevent this from occurring or restart replication when it stalls. We have recently discovered a novel human lesion bypass polymerase in human cells called PrimPol and shown that this protein, together with other cellular factors, plays an important role in helping the cell's replication machinery to bypass DNA damage it encounters during every round of cell division thus ensuring efficient genome replication. In particular, we have shown that loss of PrimPol leads to replication slowing, particularly past lesions produced by UV light, suggestive that it is required for efficient replication through these kinds of DNA damage. In this programme, we are proposing to identify how these molecular machines are able to bypass DNA damage, what are the cellular and organismal consequences of deletion or mutations in this gene (e.g. diseases associations) and, finally, how does PrimPol co-operate with other bypass proteins to ensure that replication proceeds in a faithful and complete fashion.The accumulation of mutations can lead to uncontrolled cell growth that leads to the development of diseases, such as cancer. It is therefore important to understand how cells respond when the replication machinery stops at sites of damage. An "Achilles heel" of cancer cells is that they grow more rapidly than other cells in our body and thus they replicate their DNA more often. Because of this, many cancer treatments deliberately introduce damage to DNA replication in order to selectively slow/kill cancer cells. We hope that, by understanding how the replication machinery tolerates such damage, we may be able to increase the efficiency of cancer treatments by finding ways of making cancer cells even more likely to be killed by drugs that block DNA replication.