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.
Highlights
Ataxia oculomotor apraxia type 2 (AOA2), a severe form of autosomal recessive cerebellar ataxia (ARCA) is characterised by progressive cerebellar atrophy and peripheral neuropathy, oculomotor apraxia and elevated a-fetoprotein [1,2]
Senataxin plays a role in transcription regulation by its ability to modulate RNA Polymerase II (Pol II) binding to chromatin and through its interaction with proteins involved in transcription [6]. mRNA splicing efficiency, splice site selection, and transcription termination were all defective in senataxindeficient cells [6]
Senataxin localises with DNA damage response proteins to the sex chromosomes To investigate in more detail the role of senataxin in meiosis, we studied its localization by performing immunostaining on Setx+/+ spermatocyte spreads
Summary
Ataxia oculomotor apraxia type 2 (AOA2), a severe form of autosomal recessive cerebellar ataxia (ARCA) is characterised by progressive cerebellar atrophy and peripheral neuropathy, oculomotor apraxia and elevated a-fetoprotein [1,2]. A role for senataxin has been described at the interface between transcription and the DNA damage response [11] They revealed that senataxin forms nuclear foci in S/G2 phase cells and these foci increased in response to DNA damage and impaired DNA replication. Evidence has been provided for the association of the yeast ortholog of senataxin, Sen, with DNA replication forks across RNA polymerase II transcribed genes [12]. These data demonstrate a co-ordinating role for Sen between replication and transcription
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