Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.
A defective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome.
Suraweera
Amila
A
Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia.
Becherel
Olivier J
OJ
Chen
Philip
P
Rundle
Natalie
N
Woods
Rick
R
Nakamura
Jun
J
Gatei
Magtouf
M
Criscuolo
Chiara
C
Filla
Alessandro
A
Chessa
Luciana
L
Fusser
Markus
M
Epe
Bernd
B
Gueven
Nuri
N
Lavin
Martin F
MF
D001072:Apraxias / Q000209:etiology / Q000473:pathology; D001259:Ataxia / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004265:DNA Helicases; D004260:DNA Repair; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D064251:Multifunctional Enzymes; D018384:Oxidative Stress; D020365:RNA Helicases / Q000502:physiology*
D064251:Multifunctional Enzymes; D006861:Hydrogen Peroxide; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases