Abstract
Disruption of the Setx gene, defective in ataxia oculomotor apraxia type 2 (AOA2) leads to the accumulation of DNA/RNA hybrids (R-loops), failure of meiotic recombination and infertility in mice. We report here the presence of R-loops in the testes from other autosomal recessive ataxia mouse models, which correlate with fertility in these disorders. R-loops were coincident in cells showing high basal levels of DNA double strand breaks and in those cells undergoing apoptosis. Depletion of Setx led to high basal levels of R-loops and these were enhanced further by DNA damage both in vitro and in vivo in tissues with proliferating cells. There was no evidence for accumulation of R-loops in the brains of mice where Setx, Atm, Tdp1 or Aptx genes were disrupted. These data provide further evidence for genome destabilization as a consequence of disrupted transcription in the presence of DNA double strand breaks arising during DNA replication or recombination. They also suggest that R-loop accumulation does not contribute to the neurodegenerative phenotype in these autosomal recessive ataxias.
Highlights
The autosomal recessive cerebellar ataxias (ARCAs) are a diverse group of disorders arising from defects in genes involved in the response to DNA damage; mitochondrial function and those controlling different levels of metabolic and other cellular processes [1,2]
Accumulation of R-loops in germ cells of ARCA mouse models correlates with infertility Since infertility is frequently associated with these disorders, we initially examined the testes for evidence of these structures
Recent evidence suggests that senataxin plays a central role at the interface between transcription, DNA replication and genetic recombination in resolving R-loops to minimise the risk of genome instability [21,23,24]
Summary
The autosomal recessive cerebellar ataxias (ARCAs) are a diverse group of disorders arising from defects in genes involved in the response to DNA damage; mitochondrial function and those controlling different levels of metabolic and other cellular processes [1,2]. Disruption of this gene in mice leads to age-dependent cerebral atrophy and neurons from Tdp12/ 2 cells fail to rapidly repair DNA SSB at Topo complexes [18] Another member of this group, ataxia oculomotor apraxia type 2 (AOA2) is characterised by sensitivity to DNA damaging agents [19,20]. The genomic instability that occurs in AOA2 cells appears to result from the accumulation of DNA/
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