Understanding how putting the hand brake on genes could halt cancer

Genes in the human genome are made of DNA. Upon gene expression, a segment of DNA is copied into another molecule called RNA. When gene regulation goes wrong, diseases like cancer can occur. Therefore, knowing how enzymes — highly efficient protein nanomachines — work to switch genes on and off enables the development of new drugs and diagnostics.

One way this occurs is when human genes are turned off, the cell "parks" them in a repressed state and these genes can then be kept parked in this repressed state for either a short time or for years, even for the entire lifetime of the cell or the person.

The machinery that ensures genes will stay off is named 'polycomb' and its role is similar to that of a handbrake in a car ensuring these genes will remain parked off, for as long as their product is not needed.

In a study published today in the journal, Nature Communications by Associate Professor Chen Davidovich from the Monash University Biomedicine Discovery Institute and his team determined how one of the components of this polycomb system — a protein called PALI1 — carry out its task.

The researchers discovered that PALI1 is crucial in shepherding other parts of the polycomb machinery to wherever the gene is that needs switching off or “parking”. Importantly the scientists also discovered the mechanism PALI1 uses to trigger the cascade of events required for gene repression.

According to Associate Professor Davidovich, “just like the handbrake in a car, the polycomb machinery is made up of many components of different structures and tasks, with a single broken part could lead to a disaster.”

For instance, cancer cells use the polycomb machinery to shut down genes that would, under normal conditions, prevent the growth of these cancer cells. “From a patient’s point of view, this is a disaster: it is equivalent to pulling off the car's handbrake while driving full speed on the highway – the cancer cells use polycomb mechanisms to switch off those pathways that would normally eradicate them, allowing the cancer to spread,” Associate Professor Davidovich said.

There are currently pharmaceutical companies developing inhibitors for polycomb group proteins used by cancer cells, with one anticancer drug in clinical use. According to the researchers - while these drugs are effective, one of the problems with them is that they targeting many components of the polycomb machinery, which prompt risks of toxicity and serious side effects, like a risk of the development of second cancer.

The Monash research team aims to identify components of gene repressing factors that could be served as targets for next-generation drugs that would be both effective and safe. “Using the car analogy - current drugs completely knock off the handbrake, taking away the risk of crashing on the highway but making it recklessly dangerous to park. What we are hoping to find is more specific aspects of the polycomb machinery that could be targeted by future drugs,” he said.

“Based on our results, we believe that the PALI1 and similar proteins could be good targets for drugs that will weaken the polycomb machinery in cancer cells but without preventing them from doing most of their tasks in healthy cells.”

Read the full paper in Nature Communications titled:PALI1 facilitates DNA and nucleosome binding by PRC2 and triggers an allosteric activation of catalysis”

DOI: 10.1038/s41467-021-24866-3

Animation of the crystal structure of a polypeptide from PALI1 (in blue) bound to the PRC2 regulatory subunit EED (grey and yellow). © A/Prof Chen Davidovich.

Monash is home to Australia's largest network of RNA and mRNA researchers. Keep up to date with our work on life-saving vaccines and therapeutic treatments on our Monash RNA webpage.

About the Monash Biomedicine Discovery Institute at Monash University

Committed to making the discoveries that will relieve the future burden of disease, the newly established Monash Biomedicine Discovery Institute at Monash University brings together more than 120 internationally-renowned research teams. Spanning six discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection and Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia.  Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.

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