Hypermutability and error catastrophe due to defects in ribonucleotide reductase

Significance The accuracy by which cells are able to replicate their chromosomal DNA is critical for the rate by which they produce mutations. To keep the mutation rate low, cells have developed several mechanisms including accurate base selection by DNA polymerase, exonucleolytic proofreading that can excise incorrectly inserted bases, and postreplicative DNA mismatch repair. Also important are the concentrations of the deoxynucleoside-5′-triphosphates (dNTPs) that serve as direct substrates for the DNA synthesis reaction. Here, we describe a case in which certain changes in the relative levels of the four dNTPs (dATP, dTTP, dGTP, dCTP) can profoundly disturb the overall replication fidelity by impairing the efficiency of each of the three main fidelity systems, leading to a case of extreme hypermutability.