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.