Non-homologous end-joining is implicated in rapid and efficient caspofungin adaptation in Nakaseomyces glabratus
- 1University of Guelph
Abstract
Antifungal resistance in Nakaseomyces glabratus is a major clinical challenge, yet the cellular processes that shape its evolution remain poorly understood. Here, we used experimental evolution to investigate the role of the error-prone double-strand break repair pathway, non-homologous end joining (NHEJ), in adaptation to fluconazole and caspofungin. Wild-type and NHEJ-deficient (lig4{Delta}) populations were evolved under antifungal selection for 25 days. Fluconazole resistance emerged rapidly in both genetic backgrounds and was associated with recurrent PDR1 mutations and aneuploidies. In contrast, caspofungin adaptation was delayed and less efficient in lig4{Delta} populations, with several lineages failing to survive. All wild-type caspofungin-evolved isolates carried canonical FKS2 hotspot mutations, whereas lig4{Delta} isolates predominantly acquired resistance through alternative genetic pathways. Caspofungin adaptation also frequently conferred cross-resistance to fluconazole and was accompanied by changes in the abundance of ergosterol-associated proteins. Together, these findings implicate NHEJ in promoting efficient evolution of FKS-mediated echinocandin resistance and demonstrate that DNA repair capacity can shape antifungal resistance trajectories in N. glabratus.
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BibTeX
@misc{maroc2026nonhomologous,
title = {{Non-homologous end-joining is implicated in rapid and efficient caspofungin adaptation in Nakaseomyces glabratus}},
author = {L. Maroc and N. C. Gervais and M. Fogal and E. Bates and G. Westmacott and P. McQueen and S. McCorrister and C. Grant and S. Johnson and R. S. Shapiro},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763960},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763960v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Non-homologous end-joining is implicated in rapid and efficient caspofungin adaptation in Nakaseomyces glabratus
AU - L. Maroc
AU - N. C. Gervais
AU - M. Fogal
AU - E. Bates
AU - G. Westmacott
AU - P. McQueen
AU - S. McCorrister
AU - C. Grant
AU - S. Johnson
AU - R. S. Shapiro
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763960
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763960v1
AB - Antifungal resistance in Nakaseomyces glabratus is a major clinical challenge, yet the cellular processes that shape its evolution remain poorly understood. Here, we used experimental evolution to investigate the role of the error-prone double-strand break repair pathway, non-homologous end joining (NHEJ), in adaptation to fluconazole and caspofungin. Wild-type and NHEJ-deficient (lig4{Delta}) populations were evolved under antifungal selection for 25 days. Fluconazole resistance emerged rapidly in both genetic backgrounds and was associated with recurrent PDR1 mutations and aneuploidies. In contrast, caspofungin adaptation was delayed and less efficient in lig4{Delta} populations, with several lineages failing to survive. All wild-type caspofungin-evolved isolates carried canonical FKS2 hotspot mutations, whereas lig4{Delta} isolates predominantly acquired resistance through alternative genetic pathways. Caspofungin adaptation also frequently conferred cross-resistance to fluconazole and was accompanied by changes in the abundance of ergosterol-associated proteins. Together, these findings implicate NHEJ in promoting efficient evolution of FKS-mediated echinocandin resistance and demonstrate that DNA repair capacity can shape antifungal resistance trajectories in N. glabratus.
ER -