Alterations in cellular metabolism triggered by URA7 or GLN3 inactivation cause imbalanced dNTP pools and increased mutagenesis

Abstract

Significance The duplication of the genetic information (DNA) requires high accuracy to prevent potentially deleterious genetic alterations (mutations). The fidelity of this reaction depends on DNA polymerase selectivity and proofreading functions, postreplicative mismatch repair (MMR), and the abundance of dNTPs, the building blocks of DNA. Here, in a genome-wide screen in budding yeast, we uncovered a group of genes required for high-fidelity DNA replication. When these genes are absent, cells are prone to incorporate incorrect nucleotides, and consequently they heavily rely on DNA polymerase functions and MMR to prevent severe hypermutability. These findings suggest that similar genetic interactions could play a role in human cancer, where inactivation of these genes might act as “minidrivers” that facilitate tumor evolution.