Setx, also known as senataxin, is an RNA/DNA helicase. It plays crucial roles in transcriptional regulation, the DNA damage response, and autophagy regulation by resolving R-loop structures. R-loops are RNA-DNA-hybrid-containing nucleic acids involved in various cellular processes like transcription, DNA repair, and telomere maintenance [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. Such abnormal R-loop processing and innate immune activation may contribute to diseases like neurodegeneration and cancer [1]. In Setx-depleted cells, decreased R-loop accumulation was seen, along with an inhibition of autophagy progression, accumulation of ubiquitinated proteins, reduced ability to clear protein aggregates, and mitochondrial defects. Similar autophagy pathway perturbations were found in AOA2 patient fibroblasts, suggesting a role for Setx in autophagy-related disease mechanisms [2].

In conclusion, Setx is essential for maintaining normal cellular functions by resolving R-loops and regulating autophagy. Its malfunction, as studied through depletion models, is linked to neurodegenerative diseases such as ataxia oculomotor apraxia type 2 and potentially other disorders related to abnormal R-loop processing and autophagy dysregulation.