title: Senataxin controls meiotic silencing through ATR activation and chromatin remodeling.
abstract: Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA-DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx (-/-) pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration.
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Herston, Brisbane, QLD, Australia.
authors.forename: Abrey J
authors.initials: AJ
authors.lastname: Yeo
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, QLD, Australia; School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Brisbane, QLD, Australia.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research (UQCCR) , Brisbane, QLD, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Luff
authors.affiliation: Children's Medical Research Institute, The University of Sydney , Westmead, NSW, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Graham
authors.affiliation: Cancer and Ageing Research Program, Faculty of Health, Queensland University of Technology , Brisbane, QLD, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Richard
authors.affiliation: The University of Queensland, UQ Centre for Clinical Research (UQCCR), Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Herston, Brisbane, QLD, Australia.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
keywords: DNA damage repair; chromatin remodeling; meiosis; senataxin; transcription