title: Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.
abstract: Ataxia oculomotor apraxia type 2 (AOA2) is an autosomal recessive neurodegenerative disorder characterized by cerebellar ataxia and oculomotor apraxia. The gene mutated in AOA2, SETX, encodes senataxin, a putative DNA/RNA helicase which shares high homology to the yeast Sen1p protein and has been shown to play a role in the response to oxidative stress. To investigate further the function of senataxin, we identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II. Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin deficient cells and this was accompanied by decreased transcription of these genes, suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 and 2. Splicing efficiency of specific mRNAs and alternate splice-site selection of both endogenous genes and artificial minigenes were altered in senataxin depleted cells. These data suggest that senataxin, similar to its yeast homolog Sen1p, plays a role in coordinating transcriptional events, in addition to its role in DNA repair.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: Amila
authors.initials: A
authors.lastname: Suraweera
authors.forename: YiChieh
authors.initials: Y
authors.lastname: Lim
authors.forename: Rick
authors.initials: R
authors.lastname: Woods
authors.forename: Geoff W
authors.initials: GW
authors.lastname: Birrell
authors.forename: Talat
authors.initials: T
authors.lastname: Nasim
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D017398:Alternative Splicing; D002524:Cerebellar Ataxia / Q000201:enzymology* / Q000235:genetics; D004247:DNA / Q000378:metabolism; D004265:DNA Helicases; D004260:DNA Repair; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D064251:Multifunctional Enzymes; D015840:Oculomotor Nerve Diseases / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D064251:Multifunctional Enzymes; D012322:RNA Precursors; D004247:DNA; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases