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

了解 PrimPol 在真核细胞基因组复制过程中损伤耐受中的作用

基本信息

批准号：
BB/M008800/1
负责人：
Aidan Doherty
金额：
$ 111.87万
依托单位：
University of Sussex
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM008800%2F1
关键词：
Understanding role PrimPol damage tolerance

项目摘要

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.

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具有简单的重复结构，由两条互补的DNA链组成，它们形成长的，类似于双螺旋的结构，构成基因组。我们的基因组被包装成染色体，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。细胞产生大量的蛋白质，负责“影印”这一DNA蓝图。负责精确复制我们遗传密码中数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，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，其作用是防止这种情况发生或在它停止时重新启动复制。我们最近在人类细胞中发现了一种名为PrimPol的新型人类病变旁路聚合酶，并表明这种蛋白质与其他细胞因子一起在帮助细胞的复制机制绕过它在每一轮细胞分裂期间遇到的DNA损伤方面起着重要作用，从而确保有效的基因组复制。特别是，我们已经证明PrimPol的丢失会导致复制减慢，特别是过去由UV光产生的损伤，这表明它是通过这些类型的DNA损伤进行有效复制所必需的。在这个项目中，我们打算确定这些分子机器如何能够绕过DNA损伤，这种基因的缺失或突变会对细胞和生物体产生什么影响（例如疾病协会），最后，PrimPol是如何与其他旁路蛋白一起运作，以确保复制以忠实和完整的方式进行。突变的积累会导致细胞生长失控，疾病的发展，如癌症。因此，重要的是要了解当复制机制在损伤部位停止时细胞如何反应。癌细胞的“致命弱点”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它们的DNA。正因为如此，许多癌症治疗故意对DNA复制造成损伤，以选择性地减缓/杀死癌细胞。我们希望，通过了解复制机制如何耐受这种损伤，我们可能能够通过找到使癌细胞更有可能被阻断DNA复制的药物杀死的方法来提高癌症治疗的效率。