The Mutator Phenotype: Adapting Microbial Evolution to Cancer Biology

The mutator phenotype hypothesis was postulated almost 40 years ago to reconcile the observation that while cancer cells display widespread mutational burden, acquisition of mutations in non-transformed cells is a rare event. Moreover, it also suggested that cancer evolution could be fostered by increased genome instability. Given the evolutionary conservation throughout the tree of life and the genetic tractability of model organisms, yeast and bacterial species pioneered studies to dissect the functions of genes required for genome maintenance (caretaker genes) or for cell growth control (gatekeeper genes). In this review, we first provide an overview of what we learned from model organisms about the roles of these genes and the genome instability that arises as a consequence of their dysregulation. We then discuss our current understanding of how mutator phenotypes shape the evolution of bacteria and yeast species. We end by bringing clinical evidence that lessons learned from single-cell organisms can be applied to tumor evolution.