Every cell in the body carries a set of molecular switches that keep genes turned off, and this project will work out exactly how two of those switches—enzymes called HDAC1 and HDAC2—do their job. The problem is that while drugs blocking these enzymes are already used against cancer, no one knows precisely how they work in healthy cells, which makes it hard to predict side effects or design better treatments. The researchers have created cells that lack both enzymes at once, causing the cells to die, proving the enzymes are essential for survival. They will now add back normal or mutated versions of HDAC1 to see which parts of the enzyme are critical, and use X-ray crystallography to visualise the enzyme’s molecular structure when bound to a partner protein. This is fundamental science: it will not produce a new drug tomorrow. But understanding the exact shape and mechanism of these enzymes could eventually allow chemists to design drugs that disable HDAC1 and HDAC2 more precisely, killing cancer cells while sparing healthy tissue.
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'Histone deacetylase' (HDAC) enzymes are present in all cells of the body. Their function is to switch genes 'off', and make sure they stay 'off'. My lab studies how HDACs do this and which, amongst the 25,000 genes in each cell, are selected for inactivation. HDAC enzymes also represent an exciting medical opportunity because they are 'druggable'. Already, drugs which inhibit HDAC activity are being used in the clinic as anti-cancer agents, and are being further developed for their beneficial effects on dementia and anti-inflammatory properties. There is therefore a compelling applied, as well as academic motivation for studying their physiological roles. In order to assess their potential as pharmacological targets, we need an improved understanding of how individual HDAC enzymes work in normal cells. In this study we intend study two closely related HDAC enzymes, HDAC1 and HDAC2. One of the best methods for understanding how an enzyme works is to generate mutant cells in which the specific enzyme has been inactivated, or 'knocked-out'. These 'knock-out' cells can then be examined for changes in their characteristics, lack of growth for instance, which can then be attributed to the function of that particular enzyme. Previously, we have generated 'knock-out' cells for HDAC1 and HDAC2 alone, but their function is overlapping, and so the effects on cell growth were small. To get around this, we have generated cells in which HDAC1 and 2 can be removed at the same time, so called 'double knock-out' cells. Early experiments indicate that loss of both enzymes causes cells to die, indicating that their activity is essential. Using DNA technology it is possible to add back normal or mutated forms of HDAC1 to prevent the double knock-out cells from dying and then ask, which parts of the enzyme are important for its function? In related experiments, we also intend to visualize the actual molecular structure of HDAC1 bound to a molecule called MTA1, using a technique called X-ray crystallography. The interaction of HDAC1 with other molecules in the cell is fundamental to their function. By understanding the molecular basis of these interactions we can better understand how HDAC enzymes work in normal and cancer cells, and potentially use that knowledge to design new drugs to prevent them from working. The ability to stop HDAC1 and 2 from working, as seen in our double knock-out cells, causes cells to stop growing and die, making them excellent drug targets in the search for improved anti-cancer agents.
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