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p53 controls cell metabolism to prevent genomic instability

p53 has long been called the “guardian of the genome,” but how is this tumour suppressor protein maintaining genomic stability in cells? A recent study, published in Cell Reports, highlights an important crosstalk between p53-dependent metabolic control and epigenetic regulation, which subsequently impacts genomic integrity.

The protective power of p53

p53 is an important protein that has many roles in protecting cells from genomic changes that can lead to cancer. We know how important the protein is since mutations in the p53 gene occur in almost half of all human cancers.

One of the roles of the p53 protein is to ensure correct DNA replication during cell division to maintain genomic stability. In this study, conducted by a research group at the University of Konstanz and headed by Professor Ivano Amelio, the underlying mechanism of the long-suspected crosstalk between p53 and genomic stability was unravelled.

“Like in any other replication process, such as photocopying a document or copying a digital file, it is disastrous if the template moves or is changed while the copy is being made. For this reason, genes cannot be transcribed – i.e., used as templates for proteins – while the DNA is being copied,” said Amelio. “Normally, transcription of these areas of the genome should be kept under tight control, and p53 is the key to keeping their information locked-away by controlling metabolism in a way that renders the heterochromatin inaccessible.”

Silence of the genes

Gene silencing is controlled by epigenetic mechanisms. This means that the sequence of DNA is not affected, but the packaging is. By affecting the accessibility of replication machinery to the DNA, genes can be either “on” or “off.”

The researchers found that p53 controls cell metabolism in a way that regulates the epigenomic modifications in cells. p53 keeps DNA tightly wound by driving the synthesis of s-adenosylmethionine methyl (SAM). This molecule is used to transfer methyl groups to DNA, which causes the DNA to wind up tightly into heterochromatin. This ensures that parts of the DNA that should be “off” are kept “off,” resulting in genomic stability.

The researchers showed that in p53 deficient cells, stressful cellular environments cause epigenetic dysregulation. Uncontrolled loops form in the DNA, resulting in replication stress and genomic instability. Reintroducing SAM back into p53 deficient cells restored cellular homeostasis and genomic integrity.

Keep calm and carry p53

The mystery unravelled by this research is very important, since almost half of all human cancers have p53 gene mutations. The study has revealed why genomic instability is seen in p53-inactivated tumours, providing a new angle from which to approach cancer treatment.

 “Now we have certainty that, in these tumours, there is a problem at the metabolic level that is reflected in the integrity of the epigenome,” said Amelio. “This essential insight can direct research to identify potential new therapeutic strategies for the very frequent forms of cancers that carry p53 inactivation.”


More on these topics

Cancer / Epigenetics / Tumour Suppressor