Investigating regulation and function of the cytosine deaminase APOBEC3A during cell cycle re-entry
研究细胞周期再进入过程中胞嘧啶脱氨酶 APOBEC3A 的调节和功能
基本信息
- 批准号:BB/V010271/1
- 负责人:
- 金额:$ 78.15万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2021
- 资助国家:英国
- 起止时间:2021 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
One way in which our bodies fight viral infections is to attack viral genomes (either DNA or RNA, depending on the virus) when viruses enter our cells and attempt to replicate. One protein involved in this immune response, APOBEC3A (A3A) modifies cytosine, one of the four building blocks of DNA and RNA, causing errors (mutations) and breaks in viral genes. A3A is not normally found at high levels in our cells except in certain specialised immune cells called macrophages. It is switched on in response to infection and plays an important role in protecting us from a range of viruses, however it is also activated in inflammatory conditions including eczema and psoriasis. Although A3A helps to defend us from viral infections, this protection comes at a cost, as we and others have shown that it can turn against our own genes, generating mutations that cause cancer. Numerous studies have confirmed that this process occurs in a large proportion of cancers, particularly those arising in the tissues (epithelia) that line the mouth and throat, lung, breast, bladder and cervix. Not only does A3A mutate our DNA during cancer development but it appears that A3A can continue to act in this rogue fashion while patients are receiving chemotherapy; driving drug-resistance and ultimately, treatment failure. This knowledge has stimulated initiatives in academia and industry to develop A3A inhibitors; drugs that could block this mutagenic activity in patients receiving chemotherapy, thereby preventing tumours from becoming resistant to the therapy. While this approach holds the potential to improve outcomes for millions of cancer patients, there is much we do not yet know about the way in which A3A is controlled and about the functions that it performs in the normal, healthy epithelial cells from which A3A-mutated cancers develop. Without this knowledge, we have little idea of what triggers rogue A3A activity, or what the side-effects of inhibiting A3A activity might be in patients. In this proposal, we set out a series of experiments to address these questions, based on three key findings that we have made from studying A3A in cultured human epithelial cells. 1) We have discovered that by mimicking a wound-healing response in epithelial cells, we can switch the A3A gene on to levels far higher than those previously seen in these cells and that remains at very high levels as these cells replicate their DNA, a time at which the DNA is potentially vulnerable to rogue A3A activity. 2) By deleting the A3A gene in epithelial cells, we have uncovered a previously unknown role for A3A in regulating the rate at which these cells divide, a role that is critical to understand if we are to anticipate the effects of targeting A3A for cancer therapy. 3) Recent studies have demonstrated that A3A can modify many cellular messenger RNAs, the intermediate transcripts that allow our genes to be translated into proteins but the significance of this activity remains unclear. We observe a very strong induction of this RNA-editing activity when we activate A3A in epithelial cells.Based on these novel observations, we will use our unique tools to identify in detail how the A3A gene is switched on in epithelial cells that have been stimulated to divide and will establish the role that A3A plays in regulating this process. We will conduct a comprehensive survey of A3A-mediated RNA editing events and will test our hypothesis that this activity allows A3A to change the rate at which key proteins are made.This project will result in a step-change in our knowledge of A3A regulation and function, its importance in normal epithelial biology and in pathologies ranging from inflammation to viral infections and cancer. This knowledge will be vital if we are to successfully harness A3A as a drug target. It will also address a fundamental question regarding the role of A3A-mediated RNA editing in controlling how our genes are expressed.
我们的身体对抗病毒感染的一种方式是当病毒进入我们的细胞并试图复制时攻击病毒基因组(DNA或RNA,取决于病毒)。APOBEC 3A(A3 A)是参与这种免疫反应的一种蛋白质,它修饰DNA和RNA的四个组成部分之一胞嘧啶,导致病毒基因的错误(突变)和断裂。除了某些称为巨噬细胞的特殊免疫细胞外,A3 A通常不会在我们的细胞中以高水平存在。它在感染时被打开,在保护我们免受一系列病毒的侵害方面起着重要作用,但它也在包括湿疹和牛皮癣在内的炎症条件下被激活。虽然A3 A有助于保护我们免受病毒感染,但这种保护是有代价的,因为我们和其他人已经证明它可以对抗我们自己的基因,产生导致癌症的突变。许多研究已经证实,这一过程发生在很大比例的癌症中,特别是那些出现在口腔和喉咙、肺、乳腺、膀胱和子宫颈的组织(上皮细胞)中的癌症。A3 A不仅在癌症发展过程中使我们的DNA发生突变,而且在患者接受化疗时,A3 A似乎可以继续以这种流氓方式发挥作用;驱动耐药性,最终导致治疗失败。这一知识刺激了学术界和工业界开发A3 A抑制剂的倡议;这些药物可以阻止接受化疗的患者的这种诱变活性,从而防止肿瘤对治疗产生抗药性。虽然这种方法有可能改善数百万癌症患者的预后,但我们对A3 A的控制方式以及它在A3 A突变癌症发展的正常健康上皮细胞中的功能还不了解。如果没有这些知识,我们就不知道是什么触发了A3 A的异常活性,或者抑制A3 A活性可能对患者产生什么副作用。在这项提案中,我们提出了一系列实验来解决这些问题,基于我们在培养的人类上皮细胞中研究A3 A所取得的三个关键发现。1)我们发现,通过模拟上皮细胞中的伤口愈合反应,我们可以将A3 A基因的水平转换到远远高于以前在这些细胞中观察到的水平,并且在这些细胞复制它们的DNA时保持在非常高的水平,此时DNA可能容易受到流氓A3 A活性的影响。2)通过删除上皮细胞中的A3 A基因,我们发现了A3 A在调节这些细胞分裂速率方面的一个先前未知的作用,如果我们要预测靶向A3 A对癌症治疗的影响,这一作用对于理解至关重要。3)最近的研究表明,A3 A可以修饰许多细胞信使RNA,这些中间转录物允许我们的基因被翻译成蛋白质,但这种活性的意义尚不清楚。当我们激活上皮细胞中的A3 A时,我们观察到这种RNA编辑活性的强烈诱导。基于这些新的观察结果,我们将使用我们独特的工具来详细确定A3 A基因是如何在刺激分裂的上皮细胞中打开的,并将建立A3 A在调节这一过程中的作用。我们将对A3 A介导的RNA编辑事件进行全面调查,并将测试我们的假设,即这种活动允许A3 A改变关键蛋白质的合成速率。该项目将导致我们对A3 A调节和功能的认识发生重大变化,其在正常上皮生物学和从炎症到病毒感染和癌症的病理学中的重要性。如果我们要成功地利用A3 A作为药物靶点,这些知识将是至关重要的。它还将解决关于A3 A介导的RNA编辑在控制我们的基因表达方面的作用的基本问题。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
BK polyomavirus (BKPyV) is a risk factor for bladder cancer through induction of APOBEC3-mediated genomic damage
BK 多瘤病毒 (BKPyV) 通过诱导 APOBEC3 介导的基因组损伤而成为膀胱癌的危险因素
- DOI:10.1101/2021.05.13.443803
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Baker S
- 通讯作者:Baker S
Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma
分化信号通过 GRHL3 在鳞状上皮和鳞状细胞癌中诱导 APOBEC3A 表达
- DOI:10.21203/rs.3.rs-3997426/v1
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Fenton T
- 通讯作者:Fenton T
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Tim Fenton其他文献
Molecular Cloning of CoA Synthase: THE MISSING LINK IN CoA BIOSYNTHESIS
- DOI:
10.1074/jbc.c200195200 - 发表时间:
2002-06-21 - 期刊:
- 影响因子:
- 作者:
Alexander Zhyvoloup;Ivan Nemazanyy;Aleksei Babich;Ganna Panasyuk;Natalya Pobigailo;Mariya Vudmaska;Valeriy Naidenov;Oleksandr Kukharenko;Sergiy Palchevskii;Liliya Savinska;Galina Ovcharenko;Frederique Verdier;Taras Valovka;Tim Fenton;Heike Rebholz;Mong-Lien Wang;Peter Shepherd;Genadiy Matsuka;Valeriy Filonenko;Ivan T. Gout - 通讯作者:
Ivan T. Gout
Tim Fenton的其他文献
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{{ truncateString('Tim Fenton', 18)}}的其他基金
Investigating regulation and function of the cytosine deaminase APOBEC3A during cell cycle re-entry
研究细胞周期再进入过程中胞嘧啶脱氨酶 APOBEC3A 的调节和功能
- 批准号:
BB/V010271/2 - 财政年份:2022
- 资助金额:
$ 78.15万 - 项目类别:
Research Grant
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