Fungal DNA damage repair: from model to driver of virulence and AMR

Maintaining genome integrity is essential for survival across all forms of life. Consequently, DNA damage response (DDR) mechanisms are evolutionarily ancient and broadly conserved. Despite their importance as major pathogens of humans, plants, and animals, fungal DDR mechanisms have primarily been studied as model systems to simplify and advance our understanding of DDRs in humans. Antifungal resistance is a major contributor to mortality from human fungal infections, which are associated with an estimated 3.8 million deaths annually. The ability of fungi to balance spontaneous production of beneficial mutations with the preservation of genomic integrity has emerged as a potential mechanism underlying the acquisition of antifungal resistance. In addition, several components of DNA damage repair pathways play direct roles in the virulence of fungal pathogens. In the present review, we provide an overview of DDR pathways, their function and conservation, and highlight specific roles in contributing to genome plasticity, adaptation, virulence, and the emergence of antifungal resistance.