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

DNA编码了制造蛋白质的蓝图，这些蛋白质是细胞正常活动和生长所必需的重要组成部分和工作成分。许多癌症起源于DNA中被称为“突变”的“错误”。这些“错误”可以改变蛋白质的种类和/或改变它们的功能，通常是以不希望的方式。这些DNA“错误”的后果可能包括不受控制的细胞生长和细胞对其他组织和器官的异常入侵，这些影响可能会破坏器官的正常功能。相反，许多抗癌治疗，包括一些化学疗法和放射疗法，通过破坏癌细胞的DNA来杀死癌细胞。选择性杀死癌细胞，同时保留非癌组织是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的非癌细胞的意外、异常和非特异性影响的直接后果。我们的细胞已经发展出多种复杂的综合防御，以保护和保持其DNA的完整性。我们仍在发现新的防御措施，并进一步了解这些措施是如何共同发挥作用的。我们的研究发现了抑制/阻止一类被称为“亲环蛋白”的蛋白质正常工作的意想不到的影响。抑制亲环蛋白会损害细胞正常修复DNA“错误”和有效分裂的能力。蛋白质是三维结构，亲环蛋白与其他蛋白质结合，引起其结构的局部变化，从而改变目标蛋白质的活性。这被认为是一种以可控和精确的方式调节蛋白质功能的正常方式，类似于开关的打开/关闭。然而，我们并不完全了解这对正常细胞的影响。例如，直到现在，我们甚至不知道亲环蛋白的相互作用伙伴的身份。利用复杂的捕获和鉴定技术，我们首次鉴定了几个亲环蛋白结合伙伴。出乎意料的是，其中许多通常具有修复DNA的功能。这为了解亲环蛋白在细胞内的实际作用提供了新的基础。重要的是，当我们通过基因工程人为地破坏其中一个亲环蛋白时，我们使细胞对某些抗癌药物的杀伤变得敏感。重要的是，我们还发现亲环蛋白抑制选择性地杀死一种形式的乳腺癌细胞（三阴性）。环孢素A （Cyclosporin 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。它通过抑制亲环蛋白起作用。我们发现CsA会导致DNA断裂，它也会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蛋白抑制剂，主要是作为抗HIV/丙型肝炎的药物。这些已有的药物可能代表有效的新的特定癌症治疗方法。如果得到证实，这可以避免开发新的抗癌药物的漫长而昂贵的过程，并更快地将治疗方法投入临床。

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.