Oxford scientists have discovered a key underlying cause of a range of serious conditions including cancers and Motor Neurone Disease (MND). It’s important because if you know why something happens, you can try to do something about it and you are a lot closer to fixing it. So it was overwhelming when Professor Kristijan Ramadan and his team at Oxford’s Department of Oncology discovered that a naturally-occurring, but faulty, ‘protein plough’ is linked to a range of very serious conditions.
Professor Ramadan explains that, if the body is working properly, proteins swoop in to repair lesions or damage to the DNA. Lesions can occur because of drinking, smoking, during illness or because of medicines.
what his team discovered is that a protein called Topoisomerase 1, which comes in to repair damage to the DNA, can become toxic, if it sticks (covalent attachment) to the DNA.
TEX264 is an endoplasmic reticulum (aka ER) transmembrane protein TEX264 acts as a major receptor for autophagic degradation of the ER (aka ER-phagy)
The body has its own little ‘protein plough’ which should remove proteins before they become a problem. In more complex terms, specialized DNA repair machinery composed of the :
p97 ATPase
SPRTN protease (protein plough)
autophagy receptor TEX264
should tackle the linked protein-DNA toxic product.
Professor Ramadan explains, the protein must be transitory only, if it remains on the surface of the DNA for too long, it can become entangled, difficult to remove, and potentially toxic. Problems arise, if the body’s natural plough does not clear away the protein (or if it clears away proteins too rapidly before they have a chance to repair the lesion).
The implications are potentially immense. Pathological accumulation of the protein, also known as Topoisomerase 1-cleavage-complex (Top1cc), is linked both to neurodegeneration and cancer. Faulty ‘protein ploughs’ can cause or undermine treatment for cancers and lead to debilitating conditions such as Motor Neurone Disease (ALS), and even to premature ageing. In the case of some cancers, the super-functional ‘protein plough’ can undermine chemotherapy treatment, by clearing it away from the DNA before it can be effective. Chemotherapy prevents cancer cells replicating. If it is cleared away, by an over-zealous plough, the cancer treatment will be ineffective and there is much greater possibility of metastases.
The breakthrough, published this week at https://www.nature.com/articles/s41467-020-15000-w?error=cookies_not_supported&code=f32b5e4a-14e9-4ef8-8f5d-b0be7733ba82
ref https://www.ndmrb.ox.ac.uk/about/news/oxford-scientists-in-ground-breaking-cancer-and-mnd-discovery https://www.upi.com/Science_News/2020/03/09/Scientists-find-toolkit-to-aid-repair-of-damaged-DNA/3751583765543/
24/03/202 - Scientists reveal how proteins team up to repair DNA - published today in eLife
#als #mnd #cancer #tex264 #topoisomerase #neurological #motorneuron #diseases
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