title: Senataxin, defective in the neurodegenerative disorder ataxia with oculomotor apraxia 2, lies at the interface of transcription and the DNA damage response.
abstract: The neurodegenerative disorder ataxia with oculomotor apraxia 2 (AOA-2) is caused by defects in senataxin, a putative RNA/DNA helicase thought to be involved in the termination of transcription at RNA polymerase pause sites. RNA/DNA hybrids (R loops) that arise during transcription pausing lead to genome instability unless they are resolved efficiently. We found that senataxin forms distinct nuclear foci in S/G(2)-phase human cells and that the number of these foci increases in response to impaired DNA replication or DNA damage. Senataxin colocalizes with 53BP1, a key DNA damage response protein, and with other factors involved in DNA repair. Inhibition of transcription using α-amanitin, or the dissolution of R loops by transient expression of RNase H1, leads to the loss of senataxin foci. These results indicate that senataxin localizes to sites of collision between components of the replisome and the transcription apparatus and that it is targeted to R loops, where it plays an important role at the interface of transcription and the DNA damage response.
authors.affiliation: London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts, United Kingdom.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Yüce
authors.forename: Stephen C
authors.initials: SC
authors.lastname: West
mesh_terms: D053959:Alpha-Amanitin / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D064251:Multifunctional Enzymes; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D053959:Alpha-Amanitin; D047908:Intracellular Signaling Peptides and Proteins; D064251:Multifunctional Enzymes; D029701:Saccharomyces cerevisiae Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D012313:RNA; D004247:DNA; C542347:SEN1 protein, S cerevisiae; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases