Determining the role of the prolyl cis-trans isomerase Cyclophilin A in DNA Repair at stalled DNA replication forks.

确定脯氨酰顺反异构酶亲环蛋白 A 在停滞 DNA 复制叉处的 DNA 修复中的作用。

• 批准号: MR/T012978/1
• 负责人: Mark O'Driscoll
• 金额: $ 66.98万
• 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: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT012978%2F1
• 关键词: Determining; role; prolyl; cis; trans

DNA encodes the blueprint for making proteins, vital building blocks and working components that are essential for the cells' normal activities and growth. Many cancers originate from 'errors' in DNA called "mutations". These 'errors' can alter the kinds of proteins made and/or change their functions, often in undesirable ways. The consequences of these DNA 'errors' can include uncontrolled cell growth and abnormal invasion of cells into other tissues and organs, impacts that can disrupt the normal function of organs. Conversely many anti-cancer treatments, including some chemotherapies and radiotherapies, kill cancer cells by literally breaking their DNA. Selective killing of cancer cells whilst preserving non-cancer tissue represents the principal objective of modern cancer therapies. But, this remains a significant challenge. The adverse side-effects of some cancer treatments are a direct consequence of the unintended, aberrant and non-specific impacts of the treatments upon normal, non-cancer cells. Our cells have developed multiple, complex and integrated defences that protect and preserve the integrity of their DNA. We are still uncovering new defences and developing our understanding of how these work collectively. Our research has uncovered unanticipated impacts of inhibiting/stopping a class of proteins called "Cyclophilins" from working normally. Inhibiting Cyclophilins impairs the ability of cells to normally repair 'errors' in their DNA and to divide efficiently. Proteins are three-dimensional structures and Cyclophilins bind to other proteins, causing a localised change to their structure, which consequently alters the activity of that target protein. This is thought to represent a normal way of regulating the functions of proteins in a controlled and precise fashion, analogous to a switch being turned on/off. Nevertheless, we don't have a complete understanding of the consequences of this for normal cells. For example, until now, we did not even know the identity of Cyclophilins' interacting partners. Using a sophisticated capture and identification technology, we have for the first time identified several Cyclophilin binding partners. It transpires that many of these, unexpectedly, usually function to repair DNA. This provides the basis for a new understanding of what Cyclophilins actually do within cells. Importantly, when we artificially disrupt one of the Cyclophilins through genetic engineering, we render the cells sensitive to killing by some anti-cancer drugs. Importantly, we have also found Cyclophilin inhibition selectively kills cells from a form of Breast cancer (triple negative). Cyclosporin A (CsA) is a widely used immune modulation drug used in dermatology, ophthalmology and for transplantation. It works by inhibiting Cyclophilins. We found that CsA causes DNA breakage and that it can also prevent the cell's ability to repair these breaks. Many other Cyclophilin inhibitors that don't effect the immune system have now been developed, principally as drugs against HIV/Hepatitis C. It is plausible that these pre-existing medicines could represent effective new specific cancer therapies. If verified, this could side-step the protracted and highly expensive process of developing new cancer drugs, as well as bringing treatments into clinic more quickly.

DNA编码制造蛋白质的蓝图，蛋白质是细胞正常活动和生长所必需的重要构件和工作组分。许多癌症起源于DNA中的“错误”，称为“突变”。这些“错误”可以改变蛋白质的种类和/或改变它们的功能，通常是以不受欢迎的方式。这些DNA“错误”的后果可能包括不受控制的细胞生长和细胞异常侵入其他组织和器官，这些影响可能会破坏器官的正常功能。相反，许多抗癌治疗，包括一些化疗和放疗，通过破坏癌细胞的DNA来杀死癌细胞。选择性杀死癌细胞同时保留非癌组织代表了现代癌症治疗的主要目标。但是，这仍然是一个重大挑战。一些癌症治疗的不良副作用是治疗对正常非癌细胞的非预期、异常和非特异性影响的直接后果。我们的细胞已经形成了多种、复杂和综合的防御机制，以保护和保持其DNA的完整性。我们仍在探索新的防御机制，并逐步了解这些机制是如何共同发挥作用的。我们的研究发现了抑制/阻止一类称为“亲环素”的蛋白质正常工作的意外影响。抑制亲环素会损害细胞正常修复DNA中“错误”和有效分裂的能力。蛋白质是三维结构，亲环素与其他蛋白质结合，引起其结构的局部变化，从而改变该靶蛋白的活性。这被认为代表了以受控和精确的方式调节蛋白质功能的正常方式，类似于打开/关闭开关。然而，我们并不完全了解这对正常细胞的影响。例如，到目前为止，我们甚至不知道亲环蛋白相互作用伙伴的身份。使用先进的捕获和鉴定技术，我们首次确定了几个亲环素结合伙伴。据透露，许多这些，出乎意料的，通常功能修复DNA。这为新的理解亲环素在细胞内的实际作用提供了基础。重要的是，当我们通过基因工程人为地破坏其中一种亲环素时，我们使细胞对某些抗癌药物的杀伤敏感。重要的是，我们还发现亲环素抑制选择性地杀死一种乳腺癌（三阴性）的细胞。环孢菌素A（CsA）是一种广泛应用于皮肤科、眼科和移植的免疫调节药物。它通过抑制亲环素起作用。我们发现CsA导致DNA断裂，它也可以阻止细胞修复这些断裂的能力。现在已经开发了许多其他不影响免疫系统的亲环素抑制剂，主要是作为抗HIV/丙型肝炎的药物。这些既存药物可能代表有效的新的特定癌症疗法，这是合理的。如果得到证实，这可能会避免开发新癌症药物的长期和昂贵的过程，并更快地将治疗方法引入临床。

项目成果

A novel role for the peptidyl-prolyl cis-trans isomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex

• DOI: 10.1101/2023.06.27.546694
• 发表时间: 2023-06
• 期刊: bioRxiv
• 作者: Marisa Bedir;E. Outwin;R. Colnaghi;Lydia Bassett;I. Abramowicz;M. O’Driscoll

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles.

• DOI: 10.18632/oncotarget.28358
• 发表时间: 2023-02-07
• 期刊: Oncotarget

DTYMK is essential for genome integrity and neuronal survival.

• DOI: 10.1007/s00401-021-02394-0
• 发表时间: 2022-03
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Vanoevelen JM;Bierau J;Grashorn JC;Lambrichs E;Kamsteeg EJ;Bok LA;Wevers RA;van der Knaap MS;Bugiani M;Frisk JH;Colnaghi R;O'Driscoll M;Hellebrekers DMEI;Rodenburg R;Ferreira CR;Brunner HG;van den Wijngaard A;Abdel-Salam GMH;Wang L;Stumpel CTRM
• 通讯作者: Stumpel CTRM