Non-homologous end-joining is implicated in rapid and efficient caspofungin adaptation in Nakaseomyces glabratus

NHEJ-deficient Nakaseomyces glabratus (lig4{Delta}) shows delayed, less efficient caspofungin adaptation over 25 days, with multiple lineages failing to survive.

• Why it matters: Antifungal resistance evolves under drug pressure, but how DNA repair pathways steer these trajectories is unclear, limiting mechanistic understanding and intervention strategies.
• What they did: Wild-type and lig4{Delta} populations were experimentally evolved under fluconazole or caspofungin selection for 25 days, then isolates were genotyped and phenotyped for resistance and cross-resistance.
• The result: Wild-type caspofungin-evolved isolates carried canonical FKS2 hotspot mutations, while lig4{Delta} isolates used alternative pathways; caspofungin adaptation often produced cross-resistance to fluconazole and altered ergosterol-associated protein abundance.

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