No cell, from prokaryotic to human, can survive without the essential vitamin folate (folic acid, vitamin B9).
Folate is an enzymatic cofactor vital for the biosynthesis of RNA and DNA and, therefore, required for gene expression and cell proliferation.
Folate deprivation is known to cause anemia and developmental defects.
Fast proliferating cells, such as embryonic, malignant, and immune cells, are particularly sensitive to folate depletion, and this has been translated into effective anti-folate therapy in cancer and autoimmune diseases.
However, albeit the essentiality of folate and its potential as a target for cancer therapy, we don't know much about the physiological response of cells or organisms to folate deprivation. The cellular response to low folate is unknown (see figure below), and how some cells survive folate deprivation better than others is still a mystery.... It is not clear if and how different organs play different roles in folate homeostasis at the whole-body level: Is there a regulatory system that oversees the systemic distribution of folate? Are folate levels sensed in mammals? If yes – where, and what is the molecular mechanism of folate sensing? How come some organs, such as blood cells, fetal tissues, and tumors, consume much folate and are sensitive to its deprivation, but it is the liver and kidney that contain high levels of folate even-though they don’t require much?
These are very basic questions that are key in our ability to prevent folate-deficiency related maladies, as well as to leverage the essentiality of folate for auto-immune and cancer therapies.
A cellular response to folate deprivation allows cells to survive in conditions of low-folate.
The response might include folate sensors, effector proteins that propagate the response, and a transcriptional response that allows adaptation of the cells to the shortage in folate.
This response might differ between normal and cancer cells, and portraying the cellular response to low folate will inform new folate-related vulnerabilities of cancer cells that might be targetable.