By Dr. Liji Thomas, MD Jan 24 2020
A new study published online in January 2020 in the journal Nature Communications shows that a rare genetic mutation that gives rise to a variant of the TP53 gene called P47S causes several linked biological processes, including a lower response to the malarial toxin. Image Credit: Nechaevkon/Shutterstock.com Why is the TP53 gene important?
The TP53 gene is often-mutated, and the most commonly mutated in human cancer. It is not only a tumor suppressor gene for most forms of cancer but is a key protein for a host of cellular pathways that are affected in cancer.
Found within the nucleus, the p53 protein binds to the DNA in all cells. It is instrumental in designating DNA damage due to ultraviolet exposure, for instance, as being reparable or irreparable, in which case it prevents further replication of the damaged genome, and instead signals the cell to enter the apoptosis pathway.
If it can be repaired, the p53 protein triggers the repair pathway instead. Thus, it is crucial in preventing tumor development, and has been called “the guardian of the genome”. The P475 gene variant
It comes in several forms, some common and some rare. One of these is the P475 variant, found in Africans. This has descended to their descendants in America, the African-Americans.
An earlier study by the scientists at the same institute showed that this gene variant is linked to a higher risk of cancer in this population, because of a cell process called ferroptosis. This term refers to a mode of cell death triggered by iron, and is hence related to iron overload. Iron overload and bacterial infection
The current study in mice carrying the P475 gene variant reports another adverse effect caused by excessive iron. Macrophages in these animals show a build-up of iron within their cells, which makes them less efficient at mounting an inflammatory reaction when exposed to bacterial infection. This means the mice carrying this gene are more easily infected.
“The flip side of diminished inflammation is that these mice have a more favorable response to malaria toxin hemozoin, which is responsible for most of the lethal symptoms in the acute phase of malaria.” Farokh Dotiwala
The researchers found that this variant was much more frequently found in African Americans, using data from the Hemochromatosis and Iron Overload Screening (HEIRS) study. They then switched to a mouse model engineered to carry the human variant P475. Related Stories
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