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PrimPol is a human primase/polymerase specialized in re-starting stalled forks by repriming beyond lesions such as pyrimidine dimers, and replication-perturbing structures including G-quadruplexes and R-loops. Unlike most conventional primases, PrimPol proficiently discriminates against ribonucleotides ( NTPs ), being able to start synthesis using deoxynucleotides (dNTPs), yet the structural basis and physiological implications for this discrimination are not understood.  In silico  analyses based on the three-dimensional structure of human PrimPol and related enzymes enabled us to predict a single residue, Tyr 100 , as the main effector of sugar discrimination in human PrimPol and a change of Tyr 100  to histidine to boost the efficiency of  NTP  incorporation. We show here that the Y100H mutation profoundly stimulates  NTP  incorporation by human PrimPol, with an efficiency similar to that for dNTP incorporation during both primase and polymerase reactions  in vitro . As expected from the higher cellular concentration of  NTPs  relative to dNTPs, Y100H expression in mouse embryonic fibroblasts and U2OS osteosarcoma cells caused enhanced resistance to hydroxyurea, which decreases the dNTP pool levels in S-phase. Remarkably, the Y100H PrimPol mutation has been identified in cancer, suggesting that this mutation could be selected to promote survival at early stages of tumorigenesis, which is characterized by depleted dNTP pools.

A cancer-associated point mutation disables the steric gate of human PrimPol