J. Mendez / CNIO
CNIO researchers discover that the enzyme PrimPol works when the body must produce blood cells very quickly, for example in the event of an infection
PrimPol helps cells tolerate errors in DNA. This may be an advantage, but it may also contribute to the development of some types of leukaemia. Scientists are studying how to block PrimPol in such cases
Sometimes everything needs to be perfect, but sometimes it’s the opposite: you have to turn a blind eye, tolerate mistakes, and keep going. This principle also holds true within our cells and is important for survival. CNIO researchers have discovered that the accelerated manufacture of blood cells when we need them – to cope with an infection, for example – depends on an enzyme, PrimPol, which allows cells to tolerate errors that inevitably occur during the process.
The finding, published in the journal Molecular Cell, gives clues about how blood cancers begin and suggests new strategies to stop them.
“When cells divide, their genetic material must be duplicated, and in the process errors and breaks occur in the DNA molecule,” explains Juan Méndez, head of the CNIO DNA Replication Group. “Normally, such problems slow down cell division, but sometimes the cell must go ahead with DNA replication, like a reader who continues to progress through a text after skipping a misspelled word; mistakes will be corrected later.”
One such situation in which DNA duplication must continue is infection: the body needs the blood progenitor cells to multiply rapidly, to create to leukocytes (defence cells). But in this accelerated division, DNA breaks often occur.
The group led by Juan Méndez, in collaboration with Massimo Lopes, of the University of Zurich (Switzerland), has discovered that it is the PrimPol protein that allows the copying process to continue despite errors (faults to be corrected later by other mechanisms).
But what if PrimPol helps some cells to survive and proliferate that, by accumulating defects in their genome, become tumour cells? Researchers believe that this may be happening in some types of leukaemia. To demonstrate this, they are now looking for ways to inhibit the action of PrimPol in these tumours.
Also participating in the study were Almudena Ramiro from the National Centre for Cardiovascular Research (CNIC); Raimundo Freire from the Hospital Universitario de Canarias (HUC); and Christine Eischen from the Sidney Kimmel Cancer Center in Philadelphia (USA).
Funding: Agencia Estatal de Investigación (AEI), Spain. Swiss National Science Foundation (SNSF) and European Research Council (ERC), Switzerland. National Institutes of Health (NIH) and National Cancer Institute (NCI), USA.
Reference article: Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming. Kurt Jacobs et al. (Mol Cell. 2022).