Setx, also known as senataxin, is an RNA/DNA helicase with crucial functions in transcriptional regulation and the DNA damage response by resolving R-loop structures [2]. R-loops are RNA-DNA-hybrid-containing nucleic acids involved in nucleic acid metabolism and processes like transcription, DNA repair, and telomere maintenance [4]. Setx is associated with pathways such as autophagy regulation and the unfolded protein response, and is of great biological importance as its mutations lead to neurodegenerative disorders [2,3].

When nuclear R-loops were perturbed by depleting Setx, XPG-and XPF-dependent cytoplasmic hybrid formation was observed. These cytoplasmic hybrids are R-loop-processing products, which can bind to pattern recognition receptors cGAS and TLR3, activating IRF3 and inducing apoptosis. This was also seen in Setx-mutated cells from patients with ataxia oculomotor apraxia type 2, linking R-loop accumulation to cell death through the innate immune response [1]. Setx depletion was found to inhibit autophagy progression, leading to ubiquitinated protein accumulation, reduced ability to clear protein aggregates, and mitochondrial defects. Analysis of AOA2 patient fibroblasts also revealed autophagy pathway perturbation [2]. In hypoxia, the induction of Setx was proposed to be reliant on the PERK/ATF4 arm of the unfolded protein response, and Setx plays a role in protecting cells from DNA damage induced during transcription in hypoxia [3].

In conclusion, Setx is essential for resolving R-loops, which is vital for normal nucleic acid metabolism and cellular function. Its role in autophagy regulation and response to hypoxia-induced DNA damage is significant. The study of Setx through various models, as indicated by the findings in patient cells, helps in understanding neurodegenerative diseases like AOA2 and the impact of R-loop-related mechanisms on cell death and disease development.