SETX (senataxin) is an ATP-dependent 5'→3' DNA/RNA helicase that preferentially unwinds RNA substrates, functioning primarily in R-loop resolution and transcription termination 1. The protein resolves R-loop RNA-DNA hybrids at G-rich pause sites downstream of polyadenylation sites, enabling XRN2 recruitment for efficient RNA polymerase II transcription termination 2. SETX also regulates mRNA splicing efficiency and modulates RNA Pol II chr9 binding through interactions with transcription-associated proteins 2. Beyond transcription, SETX participates in DNA damage responses through R-loop metabolism and associates with the RNA exosome complex at transcription-induced damage sites 3. Disease relevance is substantial: mutations in SETX cause two distinct neurodegenerative disorders—dominant mutations cause juvenile-onset amyotrophic lateral sclerosis 4 (ALS4) with slow progression, while recessive mutations cause ataxia with oculomotor apraxia type 2 (AOA2) 4. ALS4-mutant mice exhibit clonally expanded CD8 T cell responses correlating with motor neuron degeneration, implicating immune dysfunction in pathogenesis 4. SETX depletion impairs autophagy progression, causing ubiquitinated protein accumulation and mitochondrial defects—mechanisms observed in AOA2 patient fibroblasts 2. Additionally, aberrant R-loop accumulation following SETX loss triggers innate immune activation through cytoplasmic RNA-DNA hybrid formation, contributing to neurodegeneration 3.