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Regulation of DNA repair pathways by monoubiquitin signals

单泛素信号对 DNA 修复途径的调节

基本信息

批准号：
MR/W025256/1
负责人：
Helen Walden
金额：
$ 183.25万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2022
资助国家：
英国
起止时间：
2022 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW025256%2F1
关键词：
Regulation DNA repair pathways monoubiquitin

项目摘要

The information required for human life is encoded in our DNA, which is copied every time cells divide. It is crucial that DNA is copied accurately, as errors and mutations can be passed on to the next generations of cells, and can give rise to many different diseases, particularly cancers. The DNA in our cells is under constant threat from DNA-damaging agents. These include external sources such as UV from sunlight, tobacco, pollution, among many more, but DNA damage also happens during normal replication, metabolism, and other physiological processes. Humans have evolved multiple different pathways for repairing the many different types of DNA damage that can occur. Several inheritable diseases arise from mutations in these pathways including ataxia telangiectasia and Fanconi Anemia. These pathways are controlled by complex signal relays to recruit the many different proteins and enzymes required to keep DNA replication an accurate, high-fidelity process. One such signalling relay is the use of monoubiquitin signals, whereby a single molecule of ubiquitin is attached to a specific position on a protein that is required for recruitment and regulation of downstream repair factors. In many cancers, tumour cells are replicating more quickly than non-cancerous cells. As such, cancer cells are vulnerable to DNA damage because of the potential to slow down or stop DNA replication. This vulnerability is exploited in medicine, with targeted DNA damage being a major form of chemotherapy and radiotherapy. However, such treatments also cause damage in other cells. Furthermore, chemotherapy encourages the rapidly dividing cells in tumours to find ways around the damage, which can lead to resistance. These mechanisms of resistance to drug treatments are not yet well understood. One possibility is that cancer cells recruit components from other repair pathways to circumvent the damage being caused by targeting one particular pathway. However, we do not yet have a full understanding of how different DNA repair pathways interact and interplay with each other. Two of these repair pathways - one for allowing bypass of DNA damage sites, and one for fixing the damage when two strands of DNA become linked to each other - are regulated by common signals that are created by a unique set of proteins. The same enzyme is required to remove the signal, a step required for completion of the repair. We hypothesise that the shared features of these pathways underpin the interplay and cooperation between pathways. We aim to dissect and define the molecular details of the synergies and collaboration between pathways, defining unique elements that are specific, and generic elements that are common. We will take an integrated approach to testing this hypothesis, uncovering the atomic details of the molecules involved in order to understand how they function, and assessing the ability of individual pathways to impact on each other in cell lines. We'd like to use our insights into the molecular components to understand the basis of the interplay, how they influence each other, and whether that deep molecular understanding can be exploited to develop strategies to target cancer cells.

人类生命所需的信息被编码在我们的DNA中，每当细胞分裂时，DNA就会被复制。准确复制DNA是至关重要的，因为错误和突变可能会传递给下一代细胞，并可能导致许多不同的疾病，特别是癌症。我们细胞中的DNA不断受到DNA损伤剂的威胁。其中包括阳光、烟草、污染等外部来源，但DNA损伤也发生在正常的复制、新陈代谢和其他生理过程中。人类已经进化了多种不同的途径来修复可能发生的许多不同类型的DNA损伤。一些遗传性疾病是由这些途径的突变引起的，包括共济失调、毛细血管扩张和范可尼贫血。这些途径由复杂的信号中继器控制，以招募许多不同的蛋白质和酶，以保持DNA复制的准确、高保真过程。一种这样的信号传递是使用单泛素信号，即单个泛素分子连接到蛋白质上的特定位置，这是招募和调节下游修复因子所需的。在许多癌症中，肿瘤细胞的复制速度比非癌症细胞更快。因此，癌细胞很容易受到DNA损伤，因为它有可能减缓或阻止DNA复制。这种脆弱性在医学上被利用，靶向DNA损伤是化疗和放射治疗的一种主要形式。然而，这样的治疗也会对其他细胞造成损害。此外，化疗鼓励肿瘤中快速分裂的细胞找到绕过损伤的方法，这可能会导致耐药性。这些药物治疗耐药的机制还没有被很好地理解。一种可能性是，癌细胞从其他修复途径招募成分，以避开针对某一特定途径造成的损害。然而，我们还没有完全了解不同的DNA修复途径是如何相互作用和相互作用的。其中两条修复途径--一条用于绕过DNA损伤部位，另一条用于在两条DNA链相互连接时修复损伤--由一组独特的蛋白质产生的共同信号调控。移除信号需要同样的酶，这是完成修复所需的一步。我们假设，这些途径的共同特征为途径之间的相互作用和合作奠定了基础。我们的目标是剖析和定义途径之间协同作用和协作的分子细节，定义特定的独特元素和共同的通用元素。我们将采取一种综合的方法来检验这一假设，揭示相关分子的原子细节，以了解它们是如何发挥作用的，并评估单个途径在细胞系中相互影响的能力。我们想利用我们对分子组成的洞察来了解这种相互作用的基础，它们是如何相互影响的，以及这种深刻的分子理解是否可以被用来开发靶向癌细胞的策略。