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

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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.