# Role of the nucleotide excision repair endonuclease XPF in the kinetoplastid parasite Trypanosoma brucei

## TL;DR

This study identifies a DNA repair protein in the parasite causing sleeping sickness and shows it is crucial for repairing DNA damage and surviving chemotherapy.

## Contribution

The study identifies and characterizes XPF, a DNA repair enzyme, in Trypanosoma brucei for the first time.

## Key findings

- XPF-deficient parasites are hypersensitive to UV light and repair DNA damage more slowly.
- TbXPF protects against DNA crosslinks caused by cisplatin and mitomycin C.
- XPF localizes to the nucleus and is essential for genome stability under genotoxic stress.

## Abstract

The nucleotide excision repair (NER) mechanism is responsible for removing bulky DNA damage, such as pyrimidine dimers induced by ultraviolet (UV) light. The NER pathway excises the damaged strand through incisions at the 5’ and 3’ ends of the damage, with the 5’ incision catalyzed by the XPF-ERCC1 endonuclease complex. Here, we identify an XPF ortholog in Trypanosoma brucei, the causative agent of human African trypanosomiasis (sleeping sickness). XPF-deficient parasites exhibit hypersensitivity to UV irradiation and a slower rate of DNA damage repair. Consistent with its role in DNA repair, XPF localizes to the nucleus, associating with nucleoplasmic and nucleolar regions. Additionally, we demonstrate that TbXPF protects against intra- and inter-strand crosslinks induced by cisplatin and mitomycin C, respectively. The presence of a functional NER pathway in trypanosomes suggests that these organisms are susceptible to replication- and transcription-blocking DNA damage in vivo. Under genotoxic stress, genome stability and parasite survival may heavily rely on DNA repair systems such as NER which, for this reason, could be an effective target for chemotherapeutic interventions.

The online version contains supplementary material available at 10.1038/s41598-025-08659-y.