title: R-loops in proliferating cells but not in the brain: implications for AOA2 and other autosomal recessive ataxias.
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.
authors.affiliation: QIMR Berghofer Medical Research Institute, Radiation Biology and Oncology Laboratory, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Abrey J
authors.initials: AJ
authors.lastname: Yeo
authors.affiliation: QIMR Berghofer Medical Research Institute, Radiation Biology and Oncology Laboratory, Brisbane, Queensland, Australia; School of Chemistry and Molecular Biology, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Olivier J
authors.initials: OJ
authors.lastname: Becherel
authors.affiliation: QIMR Berghofer Medical Research Institute, Radiation Biology and Oncology Laboratory, Brisbane, Queensland, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Luff
authors.affiliation: QIMR Berghofer Medical Research Institute, Radiation Biology and Oncology Laboratory, Brisbane, Queensland, Australia.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Cullen
authors.affiliation: Department of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore, Singapore; School of Computer Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Thidathip
authors.initials: T
authors.lastname: Wongsurawat
authors.forename: Piroon
authors.initials: P
authors.lastname: Jenjaroenpun
authors.affiliation: Department of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore, Singapore.
authors.forename: Piroon
authors.initials: P
authors.lastname: Jenjaroenpoon
authors.affiliation: Department of Genome and Gene Expression Data Analysis, Bioinformatics Institute, Singapore, Singapore; School of Computer Engineering, Nanyang Technological University, Singapore, Singapore.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kuznetsov
authors.affiliation: Department of Genetics and Tumour Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: QIMR Berghofer Medical Research Institute, Radiation Biology and Oncology Laboratory, Brisbane, Queensland, Australia; School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D049109:Cell Proliferation; D004249:DNA Damage; D004265:DNA Helicases; D004195:Disease Models, Animal; D005854:Germ Cells / Q000378:metabolism; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D064251:Multifunctional Enzymes; D020365:RNA Helicases / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D064251:Multifunctional Enzymes; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases