Friend and Foe: Genome-Wide Analysis of the Tardigrade Dsup Protein Expressed in Yeast Reveals Trade-offs of DNA Protection

Abstract

Tardigrades are among the most resilient eukaryotes known, capable of surviving a wide range of extreme conditions. While their genomes contain thousands of tardigrade-specific genes, one key contributor to their stress resistance is the Damage suppressor (Dsup) protein. Previous work showed that expression of Dsup in cancer cells reduced DNA damage caused by X-rays. This observation has sparked growing interest in Dsup across diverse model organisms. Most studies to date have focused on phenotypic outcomes, while the mechanisms and consequences of Dsup remain poorly understood. Deciphering its mechanism is crucial, especially because Dsup expression is deleterious to some cells and organisms. In this work, we show that Dsup protects yeast against a variety of DNA-damaging agents. However, this protection is not universal, and it has a fitness cost. Analysis of nucleosome occupancy of cells expressing Dsup shows that effects on chromatin are modest, without global remodeling, and transcriptome analysis reveals a robust induction of oxidative stress pathways, which might be a form of preconditioning for oxidative stress. Genome-wide screens of [~]4300 loss-of-function mutants expressing Dsup shows that deletions incompatible with Dsup are highly enriched for DNA repair processes and that under DNA damage stress, Dsup can protect some mutants in a pathway-specific manner. Our findings demonstrate that while Dsup broadly enhances resistance to genotoxic stress, it also imposes physiological costs and generates new dependencies on DNA repair and genome maintenance pathways.