It is worth mentioning that PrimPol inactivation or removal during the replication of nuclear DNA entails a significant reduction of replication fork speed, indicating its relevant role in physiological conditions. Thus, whereas PrimPol-deficient mice and siRNA-depleted human cells were viable, they show large symptoms of genomic instability, very likely related to the augmented DNA RS in these cells.

On the other hand, in the presence of RS induced by replication inhibitors or topoisomerase poisons, such as camptothecin and etoposide, PrimPol deficiency generates a strong and persistent increase in RS signaling, leading to augmented genetic instability, a hallmark of cancer cells. Altogether, our data strongly suggest that PrimPol is a novel and relevant target in cancer. Its deficiency, either due to specific inactivating mutations or to the use of specific inhibitors, in combination with other well known genotoxic agents, would lead to high replicative stress burden causing tumor cells death by replication catastrophe. Thus, another objective of our research is the analysis of human PrimPol regulation, and the characterization of human PrimPol cancer variants with altered specific activity and primase deficiency, that could have a pronostic value in cancer.

From a biotechnological perspective, we have developed a high-trhougput secreening to obtain PrimPol variants with altered specificity that could be relevant for a novel PrimPol-based DNA amplification method named TruePrime™, currently commercialized by Expedeon AG (currently 4BaseBio AG), for the diagnosis of cancer in liquid biopsies.