Probable RNA/DNA helicase involved in diverse aspects of RNA metabolism and genomic integrity. Plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription. Contributes to the mRNA splicing efficiency and splice site selection. Required for the resolution of R-loop RNA-DNA hybrid formation at G-rich pause sites located downstream of the poly(A) site, allowing XRN2 recruitment and XRN2-mediated degradation of the downstream cleaved RNA and hence efficient RNA polymerase II (RNAp II) transcription termination (By similarity). Required for the 3' transcriptional termination of PER1 and CRY2, thus playing an important role in the circadian rhythm regulation (PubMed:22767893). Involved in DNA double-strand breaks damage response generated by oxidative stress. In association with RRP45, targets the RNA exosome complex to sites of transcription-induced DNA damage (By similarity). Plays a role in the development and maturation of germ cells: essential for male meiosis, acting at the interface of transcription and meiotic recombination, and in the process of gene silencing during meiotic sex chromosome inactivation (MSCI) (PubMed:23593030). Plays a role in neurite outgrowth in hippocampal cells through FGF8-activated signaling pathways. Inhibits retinoic acid-induced apoptosis. May be involved in telomeric stability through the regulation of telomere repeat-containing RNA (TERRA) transcription (By similarity). Homodimer (By similarity). Interacts with PER2; the interaction inhibits termination of circadian target genes (PubMed:22767893). Interacts with CHD4, POLR2A, PRKDC and TRIM28. Does not interact with C14orf178. Interacts with UBE2I. Interacts (via N-terminus domain) with EXOSC9 (via C-terminus region); the interaction enhances SETX sumoylation. Interacts with NCL (via N-terminus domain). Interacts with PABPN1, PABPC1 and SF3B1. Interacts with SMN1/SMN2 and POLR2A; SMN1/SMN2 recruits SETX to POLR2A (By similarity). Most abundant in the nucleus (By similarity). Detected in granules (By similarity). Colocalized in cycling cells with FBL in the nucleolus. Localizes with telomeric DNA in a transcription-dependent manner. Under replication stress, colocalizes with a variety of DNA damage signaling and repair response proteins at distinct nuclear foci in mitotic S/G2- and G1-phase cells in a transcription- and RNA/DNA hybrid-dependent manner. Localizes at limited number of nuclear foci. Colocalizes with EXOSC9 in nuclear foci upon induction of transcription-related DNA damage at the S phase (By similarity). At pachytene stage, colocalizes predominantly to the heterochromatic XY-body of sex chromosomes with DNA damage response proteins in a BRCA1-dependent manner (PubMed:23593030). May be detected in the nucleolus only in cycling cells (PubMed:16644229). Expressed in cerebellum, hippocampus, olfactory bulb, Bergmann glial fibers, stellate cells and Purkinje cells. Expressed in the epithelial cells of the lens but not in mature lens fiber cells. Expressed in the retina (highly expressed in inner and outer segments of photoreceptors and outer plexiform layer cells but weakly expressed in the inner plexiform and ganglion cell layers). Expressed in the kidney. The N-terminus domain is necessary for S/G2 nuclear foci localization. Ubiquitinated. Sumoylated preferentially with SUMO2 or SUMO3. Mice are viable. Male germ cells proceed normally from spermatogonia up to the meiotic pachytene stage but fail to enter into spermiogenesis and form mature spermatids (PubMed:23593030), resulting in male infertility. In particular, during spermatogenesis, male germ cells accumulated DNA:RNA hybrids (R-loops), meiotic DNA double-strand breaks, and fails to produce crossovers and meiotic sex chromosome inactivation (MSCI) (PubMed:23593030). Belongs to the DNA2/NAM7 helicase family. The sequence differs from that shown because it is derived from pre-RNA.