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.
Highlights
Mutations in senataxin give rise to the autosomal recessive cerebellar disorder, ataxia oculomotor apraxia type 2 (AOA2) [1, 2], and to autosomal dominant juvenile-onset, amyotrophic lateral sclerosis 4 [3, 4]
Senataxin is SUMOylated on the XY body The various stages of meiosis can be differentiated by immunostaining for synaptonemal complex protein 3 (SCP3), a proteinaceous component of the axial element of the synaptonemal complex required for chromosomal synapsis [21]
We have previously shown that senataxin localized as a diffuse ‘cloud’ to the XY chromosomes in spermatocytes at the pachytene stage of male meiosis where it has an essential but undefined role in meiotic sex chromosome inactivation (MSCI) [20] (Figure 1a)
Summary
Mutations in senataxin give rise to the autosomal recessive cerebellar disorder, ataxia oculomotor apraxia type 2 (AOA2) [1, 2], and to autosomal dominant juvenile-onset, amyotrophic lateral sclerosis 4 [3, 4]. Senataxin localized to the XY chromosomes at the pachytene stage and abnormal diffusion of DNA damage rep (DDR) proteins into the XY chromatin domain was observed, predicting that the XY chromosomes would fail to be transcriptionally silenced in Setx−/− pachytene cells, which turned out to be the case [20]. These results pointed to a key role for senataxin in both meiotic homologous recombination and in meiotic sex chromosome inactivation (MSCI)
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