title: Senataxin plays an essential role with DNA damage response proteins in meiotic recombination and gene silencing.
abstract: Senataxin, mutated in the human genetic disorder ataxia with oculomotor apraxia type 2 (AOA2), plays an important role in maintaining genome integrity by coordination of transcription, DNA replication, and the DNA damage response. We demonstrate that senataxin is essential for spermatogenesis and that it functions at two stages in meiosis during crossing-over in homologous recombination and in meiotic sex chromosome inactivation (MSCI). Disruption of the Setx gene caused persistence of DNA double-strand breaks, a defect in disassembly of Rad51 filaments, accumulation of DNA:RNA hybrids (R-loops), and ultimately a failure of crossing-over. Senataxin localised to the XY body in a Brca1-dependent manner, and in its absence there was incomplete localisation of DNA damage response proteins to the XY chromosomes and ATR was retained on the axial elements of these chromosomes, failing to diffuse out into chromatin. Furthermore persistence of RNA polymerase II activity, altered ubH2A distribution, and abnormal XY-linked gene expression in Setx⁻/⁻ revealed an essential role for senataxin in MSCI. These data support key roles for senataxin in coordinating meiotic crossing-over with transcription and in gene silencing to protect the integrity of the genome.
authors.affiliation: Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.forename: Abrey J
authors.initials: AJ
authors.lastname: Yeo
authors.forename: Alissa
authors.initials: A
authors.lastname: Stellati
authors.forename: Evelyn Y H
authors.initials: EY
authors.lastname: Heng
authors.forename: John
authors.initials: J
authors.lastname: Luff
authors.forename: Amila M
authors.initials: AM
authors.lastname: Suraweera
authors.forename: Rick
authors.initials: R
authors.lastname: Woods
authors.forename: Jean
authors.initials: J
authors.lastname: Fleming
authors.forename: Dianne
authors.initials: D
authors.lastname: Carrie
authors.forename: Kristine
authors.initials: K
authors.lastname: McKinney
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000818:Animals; D001072:Apraxias / Q000151:congenital; D001259:Ataxia / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D055952:Cogan Syndrome / Q000235:genetics; D003434:Crossing Over, Genetic; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D020868:Gene Silencing; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D064251:Multifunctional Enzymes; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D013091:Spermatogenesis; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D002843:Chromatin; D064251:Multifunctional Enzymes; D051135:Rad51 Recombinase; C484368:SETX protein, human; C581831:SETX protein, mouse; D004265:DNA Helicases; D020365:RNA Helicases